William L. Carroll, M.D.

Clinical and laboratory biology of childhood acute lymphoblastic leukemia
Carroll, William L; Raetz, Elizabeth A
2012 Jan;160(1):10-18, Journal of pediatrics
— id: 146251, year: 2012, vol: 160, page: 10, stat: Journal Article,

EPIGENETIC REPROGRAMMING ENDOWS CHEMOSENSITIVITY IN LEUKEMIA CELL LINES
Bhatla, Teena; Wang, Jinhua; Morrison, Debra; Raetz, Elizabeth; Carroll, William
2011 JUN ;56(6):900-900, Pediatric blood & cancer
— id: 129014, year: 2011, vol: 56, page: 900, stat: Journal Article,

Augmented Therapy Improves Outcome for Pediatric High Risk Acute Lymphocytic Leukemia: Results Of Children's Oncology Group Trial P9906
Bowman, W. Paul; Larsen, Eric L.; Devidas, Meenakshi; Linda, Stephen B.; Blach, Laurie; Carroll, Andrew J.; Carroll, William L.; Pullen, D. Jeanette; Shuster, Jonathan; Willman, Cheryl L.; Winick, Naomi; Camitta, Bruce M.; Hunger, Stephen P.; Borowitz, Michael J.
2011 OCT ;57(4):569-577, Pediatric blood & cancer
Background. The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials. Procedures. Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at clay 29 of induction and correlated with outcome. Results. The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 +/- 3.7% vs. 50.6 +/- 2.4%; P = 0.0007) but similar to POG 9406 (63.5 +/- 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC >= 100,000/microliter. clay 29 marrow MRD positive (>= 0.01%) vs. negative patients had 5 year CCR rates of 37.1 +/- 7.4% vs. 72.6 +/- 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 +/- 4.6% vs.83.6 +/- 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, clay 29 MRD > 0.01%, initial WBC >= 100,000/mu l, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors. Conclusions. Augmented BFM therapy improved outcome for children with higher risk ALL. day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients. Pediatr Blood Cancer 2011;57:569-577. (C) 2011 Wiley-Liss, Inc
— id: 137027, year: 2011, vol: 57, page: 569, stat: Journal Article,

Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia
Hijiya, Nobuko; Thomson, Blythe; Isakoff, Michael S.; Silverman, Lewis B.; Steinherz, Peter G.; Borowitz, Michael J.; Kadota, Richard; Cooper, Todd; Shen, Violet; Dahl, Gary; Thottassery, Jaideep V.; Jeha, Sima; Maloney, Kelly; Paul, Jo-Anne; Barry, Elly; Carroll, William L.; Gaynon, Paul S.
2011 DEC 1 ;118(23):6043-6049, Blood
The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; >= 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705. (Blood. 2011;118(23):6043-6049)
— id: 147715, year: 2011, vol: 118, page: 6043, stat: Journal Article,

Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies
Hogan LE; Meyer JA; Yang J; Wang J; Wong N; Yang W; Condos G; Hunger SP; Raetz E; Saffery R; Relling MV; Bhojwani D; Morrison DJ; Carroll WL
2011 Nov 10;118(19):5218-5226, Blood
Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance, and identify novel targets of therapy, three high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL we evaluated gene expression, copy number abnormalities (CNA), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse, that is different for early (<36 months) and late (>/=36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse, and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all three platforms identified genes of potential interest including CDKN2A, COL6A2, PTPRO and CSMD1. While our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA and methylation data suggest a possible convergence on the WNT and MAPK pathways
— id: 137806, year: 2011, vol: 118, page: 5218, stat: Journal Article,

Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles
Loudin, M G; Wang, J; Eastwood Leung, H-C; Gurusiddappa, S; Meyer, J; Condos, G; Morrison, D; Tsimelzon, A; Devidas, M; Heerema, N A; Carroll, A J; Plon, S E; Hunger, S P; Basso, G; Pession, A; Bhojwani, D; Carroll, W L; Rabin, K R
2011 Oct;25(10):1555-1563, Leukemia
Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions
— id: 139922, year: 2011, vol: 25, page: 1555, stat: Journal Article,

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group
Matloub, Yousif; Bostrom, Bruce C.; Hunger, Stephen P.; Stork, Linda C.; Angiolillo, Anne; Sather, Harland; La, Mei; Gastier-Foster, Julie M.; Heerema, Nyla A.; Sailer, Scott; Buckley, Patrick J.; Thomson, Blythe; Cole, Catherine; Nachman, James B.; Reaman, Gregory; Winick, Naomi; Carroll, William L.; Devidas, Meenakshi; Gaynon, Paul S.
2011 JUL 14 ;118(2):243-251, Blood
Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% +/- 1.4% and 96% +/- 0.9% versus 92.6% +/- 1.2% and 96.5% +/- 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% +/- 1.3% and 97.1% +/- 0.8% versus 90.5% +/- 1.3% and 95.4% +/- 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS. (Blood.2011;118(2):243-251)
— id: 135635, year: 2011, vol: 118, page: 243, stat: Journal Article,

Treating persistent distress and anxiety in parents of children with cancer: an initial feasibility trial
Warner, Carrie Masia; Ludwig, Kristy; Sweeney, Corinne; Spillane, Clare; Hogan, Laura; Ryan, Julie; Carroll, William
2011 Jul-Aug;28(4):224-230, Journal of pediatric oncology nursing
Persistent anxiety is common among parents of children with cancer and may affect the family's well-being and adjustment. The goals of this pilot study are to determine the feasibility and potential efficacy of a brief cognitive-behavioral parent intervention aimed at reducing parental distress and anxiety related to their child's cancer diagnosis. Parents of children with cancer, at least 1 month postdiagnosis, were screened at an outpatient oncology clinic, and those reporting elevated levels of distress were offered a 4-session cognitive-behavioral intervention based on a modified version of the Surviving Cancer Competently Intervention Program-Newly Diagnosed. Five parents reporting persistent distress received the intervention. Results revealed decreases in parents' distress, state anxiety, and depressive symptoms, as well as in parents' feelings of burden associated with their children's cancer. This initial study suggests that identification of parents with prolonged heightened psychological distress is feasible and acceptable and that offering them a brief intervention within a pediatric oncology setting may be beneficial
— id: 134914, year: 2011, vol: 28, page: 224, stat: Journal Article,

Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group
Zhang, Jinghui; Mullighan, Charles G.; Harvey, Richard C.; Wu, Gang; Chen, Xiang; Edmonson, Michael; Buetow, Kenneth H.; Carroll, William L.; Chen, I-Ming; Devidas, Meenakshi; Gerhard, Daniela S.; Loh, Mignon L.; Reaman, Gregory H.; Relling, Mary V.; Camitta, Bruce M.; Bowman, W. Paul; Smith, Malcolm A.; Willman, Cheryl L.; Downing, James R.; Hunger, Stephen P.
2011 SEP 15 ;118(11):3080-3087, Blood
We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways, including B-cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2), and ADARB2 (2). The frequency of mutations within the 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1-like gene expression profile, 96% had somatic alterations in B-cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had Ras pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B-cell development/differentiation or JAK kinase alterations but had a high frequency (62%) of Ras signaling pathway mutations. These data extend the range of genes that are recurrently mutated in high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets. (Blood. 2011; 118(11):3080-3087)
— id: 137922, year: 2011, vol: 118, page: 3080, stat: Journal Article,

Vorinostat Reverses Relapse Specific Drug Resistance Gene Expression Signatures In Childhood Acute Lymphoblastic Leukemia (ALL)
Bhatla, Teena; Wang, Jinhua; Morrison, Debra J.; Zaky, Wafik T.; Raetz, Elizabeth A.; Carroll, William L.
2010 NOV 19 ;116(21):1493-1494, Blood
— id: 130870, year: 2010, vol: 116, page: 1493, stat: Journal Article,

Cancer in children and adolescents
Carroll, William L; Finlay, Jonathan L
Sudbury MA : Jones and Bartlett, 2010,
— id: 1826, year: 2010, vol: , page: , stat: ,

Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia
Harvey, RC; Mullighan, CG; Chen, IM; Wharton, W; Mikhail, FM; Carroll, AJ; Kang, HN; Liu, W; Dobbin, KK; Smith, MA; Carroll, WL; Devidas, M; Bowman, WP; Camitta, BM; Reaman, GH; Hunger, SP; Downing, JR; Willman, CL
2010 JUL 1 ;115(26):5312-5321, Blood
Gene expression profiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemia revealed 29 of 207 cases (14%) with markedly elevated expression of CRLF2 (cytokine receptor-like factor 2). Each of the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had a translocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in the pseudoautosomal region 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a 320-kb interstitial deletion centromeric of CRLF2, resulting in a P2RY8-CRLF2 fusion. One case had both IGH@-CRLF2 and P2RY8-CRLF2, and another had a novel CRLF2 rearrangement. Only 2 of 29 cases were Down syndrome. CRLF2 rearrangements were significantly associated with activating mutations of JAK1 or JAK2, deletion or mutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 for each). Within this cohort, patients with CRLF2 rearrangements had extremely poor treatment outcomes compared with those without CRLF2 rearrangements (35.3% vs 71.3% relapse-free survival at 4 years; P < .001). Together, these observations suggest that activation of CRLF2 expression, mutation of JAK kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways as important therapeutic targets in this disease. This trial was registered at www.clinicaltrials.gov as #NCT00005603. (Blood. 2010;115(26):5312-5321)
— id: 110859, year: 2010, vol: 115, page: 5312, stat: Journal Article,

Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome
Harvey, Richard C.; Mullighan, Charles G.; Wang, Xuefei; Dobbin, Kevin K.; Davidson, George S.; Bedrick, Edward J.; Chen, I-Ming; Atlas, Susan R.; Kang, Huining; Ar, Kerem; Wilson, Carla S.; Wharton, Walker; Murphy, Maurice; Devidas, Meenakshi; Carroll, Andrew J.; Borowitz, Michael J.; Bowman, W. Paul; Downing, James R.; Relling, Mary; Yang, Jun; Bhojwani, Deepa; Carroll, William L.; Camitta, Bruce; Reaman, Gregory H.; Smith, Malcolm; Hunger, Stephen P.; Willman, Cheryl L.
2010 DEC 2 ;116(23):4874-4884, Blood
To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% +/- 5.1%, compared with 63.5% +/- 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% +/- 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy. (Blood. 2010;116(23):4874-4884)
— id: 115373, year: 2010, vol: 116, page: 4874, stat: Journal Article,

GENE EXPRESSION ANALYSIS REVEALS DISTINCT SIGNATURES FOR EARLY AND LATE RELAPSE IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Hogan, L; Meyer, J; Wang, JH; Morrison, D; Yang, J; Hunger, S; Willman, C; Relling, M; Raetz, E; Bhojwani, D; Carroll, W
2010 JUN ;54(6):790-791, Pediatric blood & cancer
— id: 110438, year: 2010, vol: 54, page: 790, stat: Journal Article,

Phase 2 Results of Clofarabine In Combination with Etoposide and Cyclophosphamide In Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia
Huiya, Nobuko; Paul, Jo Anne; Borowitz, Michael J.; Thomson, Blythe; Isakoff, Michael; Silverman, Lewis B.; Steinherz, Peter G.; Kadota, Richard; Pressey, Joseph G.; Shen, Violet; Chu, Roland; Cooper, Todd; Jeha, Sima; Razzouk, Bassem I.; Rytting, Michael E.; Barry, Elly; Carroll, William L.; Gaynon, Paul
2010 NOV 19 ;116(21):378-379, Blood
— id: 130864, year: 2010, vol: 116, page: 378, stat: Journal Article,

Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia
Kang, HN; Chen, IM; Wilson, CS; Bedrick, EJ; Harvey, RC; Atlas, SR; Devidas, M; Mullighan, CG; Wang, XF; Murphy, M; Ar, K; Wharton, W; Borowitz, MJ; Bowman, WP; Bhojwani, D; Carroll, WL; Camitta, BM; Reaman, GH; Smith, MA; Downing, JR; Hunger, SP; Willman, CL
2010 FEB 18 ;115(7):1394-1405, Blood
To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate( 62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retained independent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603. (Blood. 2010; 115: 1394-1405)
— id: 107743, year: 2010, vol: 115, page: 1394, stat: Journal Article,

Gene Expression Profiling Reveals Genes Predictive of Outcome In Infant Acute Lymphoblastic Leukemia (ALL) and Distinctive Age Related Gene Expression Profiles (< 90 Days vs > 90 Days) A Children's Oncology Group Study
Kang, Huining; Wilson, Carla S.; Harvey, Richard C.; Chen, I. Ming; Murphy, Maurice H.; Atlas, Susan R.; Bedrick, Edward J.; Devidas, Meenakshi; Carroll, Andrew J.; Robinson, Blaine W.; Heerema, Nyla A.; Hilden, Joanne M.; Dreyer, Zoann E.; Camitta, Bruce; Winick, Naomi; Carroll, William L.; Felix, Carolyn A.; Reaman, Gregory H.; Hunger, Stephen P.; William, Cheryl L.
2010 NOV 19 ;116(21):183-184, Blood
— id: 130857, year: 2010, vol: 116, page: 183, stat: Journal Article,

Early Response Characteristics and Blast Cytogenetic FEatures In 5,377 Children with Standard Risk Acute Lymphoblastic Leukemia (SR-ALL) A Children's Oncology Group (COG) Study
Maloney, Kelly W.; Loh, Mignon L.; Raetz, Elizabeth; Borowitz, Michael J.; Devidas, Meenakshi; Friedmann, Alison M.; Mattano, Leonard A.; Wood, Brent; Winick, Naomi; Hunger, Stephen; Carroll, William L.
2010 NOV 19 ;116(21):184-184, Blood
— id: 130858, year: 2010, vol: 116, page: 184, stat: Journal Article,

Children with Down Syndrome (DS) and NCI Standard Risk (SR) Acute Lymphoblastic Leukemia (ALL) Have a Superior Five Year Event Free Survival (EFS) When Treated with Escalating Intravenous Methotrexate on the Children's Cancer Group (CCG) Study 1991
Matloub, Yousif; Bostrom, Bruce C.; Hunger, Stephen; Angiolillo, Anne; Devidas, Meenakshi; La, Mei; Heerema, Nyla A.; Winick, Naomi; Nachman, James; Sather, Harland; Carroll, William L.; Gaynon, Paul S.
2010 NOV 19 ;116(21):221-221, Blood
— id: 130860, year: 2010, vol: 116, page: 221, stat: Journal Article,

High Throughput Transcriptome Sequencing of Pediatric Relapsed Acute Lymphoblastic Leukemia (ALL) Identifies Relapse Specific Mutations and Expression
Meyer, Julia A.; Hogan, Laura E.; Wang, Jinhua; Yang, Jun J.; Patel, Jay; Levine, Ross L.; Hunger, Stephen P.; Raetz, Elizabeth; Mason, Christopher; Carroll, William L.
2010 NOV 19 ;116(21):1326-1326, Blood
— id: 130868, year: 2010, vol: 116, page: 1326, stat: Journal Article,

Biology and Treatment of Acute Lymphoblastic Leukemia
Pieters, R; Carroll, WL
2010 FEB ;24(1):1-+, Hematology-oncology clinics of North America
Acute lymphoblastic leukemia (ALL), the most common type of cancer in children, is a heterogeneous disease in which many genetic lesions result in the development of multiple biologic subtypes. Today, with intensive multiagent chemotherapy, most children who have ALL are cured. The many national or institutional ALL therapy protocols in use tend to stratify patients in a multitude of different ways to tailor treatment to the rate of relapse. This article discusses the factors used in risk stratification and the treatment of pediatric ALL
— id: 109832, year: 2010, vol: 24, page: 1, stat: Journal Article,

Administration of Erwinia Asparaginase (Erwinase (R)) Following Allergy to PEG-Asparaginase In Children and Young Adults with Acute Lymphoblastic Leukemia Treated on AALL07P2 Achieves Therapeutic Nadir Serum Asparaginase Activity: A Report From the Children's Oncology Group (COG)
Salzer, Wanda; Asselin, Barbara; Supko, Jeffrey; Devidas, Meenakshi; Kaiser, Nicole; Plourde, Paul V.; Winick, Naomi; Reaman, Gregory; Raetz, Elizabeth; Carroll, William L.; Hunger, Stephen
2010 NOV 19 ;116(21):882-882, Blood
— id: 134502, year: 2010, vol: 116, page: 882, stat: Journal Article,

Infant Acute Lymphoblastic Leukemias Are Pan Sensitive to Obatoclax Across molecular/Cytogenetic Subtypes, Especially MLL ENL, and gene Expression Profiles Determine Obatoclax IC50 A Report on the Children's Oncology Group (COG) P9407 Trial
Urtishak, Karen A.; Wang, Li San; Harvey, Richard; Atlas, Susan R.; Chen, I. Ming L.; Robinson, Blaine W.; Moukarzel, Lea; Cao, Kajia; Devidas, Meenakshi; Carroll, Andrew J.; Heerema, Nyla A.; Hunger, Stephen; Reaman, Gregory H.; Hilden, Joanne M.; Camitta, Bruce; Winick, Naomi; Carroll, William L.; Zhang, Alena Y.; Cory, Lori; McVeigh, Steven; Barrett, Jeffery S.; Dreyer, Zoann E.; Willman, Cheryl L.; Felix, Carolyn A.
2010 NOV 19 ;116(21):1137-1137, Blood
— id: 130866, year: 2010, vol: 116, page: 1137, stat: Journal Article,

Nelarabine May Be Safely Incorporated Into a Phase III Study for Newly Diagnosed T Lineage Acute Lymphoblastic Leukemia A Report From the Children's Oncology Group
Winter, Stuart S.; Devidas, Meenakshi; Wood, Brent; Borowitz, Michael J.; Loh, Mignon L.; Asselin, Barbara; Murphy, John; Raetz, Elizabeth; Winick, Naomi; Hunger, Stephen; Carroll, William; Dunsmore, Kimberly
2010 NOV 19 ;116(21):378-378, Blood
— id: 130863, year: 2010, vol: 116, page: 378, stat: Journal Article,

IKAROS DELETION LEADS TO CHEMOTHERAPY RESISTANCE IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
Zaky, W; Chen, Z; Meyer, J; Bhatla, T; Yang, J; Relling, M; Yang, WJ; Wang, JH; Morrison, D; Raetz, E; Carroll, W
2010 JUN ;54(6):789-789, Pediatric blood & cancer
— id: 110437, year: 2010, vol: 54, page: 789, stat: Journal Article,

Lack of Somatic Sequence Mutations In Protein Tyrosine Kinase Genes Other Than the JAK Kinase Family In High Risk B Precursor Childhood Acute Lymphoblastic Leukemia (ALL) A Report From the Children's Oncology Group (COG) High Risk (HR) ALL TARGET Project
Zhang, Jinghui; Mullighan, Charles; Harvey, Richard; Carroll, William L.; Chen, I. Ming L.; Devidas, Meenakshi; Larsen, Eric; Edmonson, Michael; Buetow, Ken; Gerhard, Daniela S.; Loh, Mignon L.; Reaman, Gregory H.; Relling, Mary V.; Smith, Malcolm A.; Downing, James R.; Willman, Cheryl L.; Hunger, Stephen
2010 NOV 19 ;116(21):1135-1135, Blood
— id: 130865, year: 2010, vol: 116, page: 1135, stat: Journal Article,

Report On Excessive Induction Toxicity in Infants with ALL Enrolled On COG Protocol AALL0631: A Children's Oncology Group Study
Brown, P; Hilden, JM; Dreyer, ZE; Winick, NJ; Salzer, W; Raetz, E; Sung, L; Zaoutis, TE; Jones, T; Devidas, M; De Lorenzo, P; Valsecchi, MG; Pieters, R; Carroll, WL; Hunger, SP
2009 NOV 20 ;114(22):1202-1202, Blood
— id: 109995, year: 2009, vol: 114, page: 1202, stat: Journal Article,

Novel targeted drug therapies I for the treatment of childhood acute leukemia
Brown, Patrick; Hunger, Steven P.; Smith, Franklin O.; Carroll, William L.; Reaman, Gregory H.
2009 APR ;2(2):145-158, Expert Review of Hematology
The cure rates for childhood acute leukemia have dramatically improved to approximately 70% overal, with treatments that include intensive cytotoxic chemotherapy and, in some cases, hematopoietic stem cell transplantation. However, many children still die of their disease or of treatment-related toxicities. Even in patients that are cured, there can be significant and, not uncommonly debilitating, acute and late complications of treatment. Improved understanding of the molecular and cellular biology of leukemia and the increasing availability of high-throughput genomic techniques have facilitated the development of molecularly targeted therapies that have the potential to be more effective and less toxic than the standard approaches. In this article, we review the progress to date with agents that are showing promise in the treatment of childhood acute leukemia, including monoclonal antibodies, inhibitors of kinases and other signaling molecules (e.g., BCR-ABL, FLT3, farnesyltransferase, mTOR and gamma-secretase), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors) and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress or are being planned for children with acute leukemia. Finally, we discuss potential challenges to the success of molecularly targeted therapy, including proper target identification, adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients
— id: 115371, year: 2009, vol: 2, page: 145, stat: Journal Article,

Masked Hypodiploidy: Hypodiploid Acute Lymphoblastic Leukemia (ALL) in Children Mimicking Hyperdiploid A
Carroll, AJ; Heerema, NA; Gastier-Foster, JM; Astbury, C; Pyatt, R; Reshmi, SC; Borowitz, MJ; Devidas, M; Linda, S; Loh, ML; Raetz, EA; Wood, B; Winick, NJ; Hunger, SP; Carroll, WL
2009 NOV 20 ;114(22):632-632, Blood
— id: 109980, year: 2009, vol: 114, page: 632, stat: Journal Article,

AAML0523: A Report From the Children's Oncology Group On the Safety of Clofarabine in Combination with Cytarabine in Pediatric Patients with Relapsed Acute Leukemia
Cooper, T; Alonzo, TA; Gerbing, RB; Perentesis, J; Whitlock, JA; Raetz, E; Carroll, WL; Gamis, AS; Razzouk, BI
2009 NOV 20 ;114(22):1196-1196, Blood
— id: 109994, year: 2009, vol: 114, page: 1196, stat: Journal Article,

Amplification of AML1 Does Not Impact Early Outcome of Children with Acute Lymphoblastic Leukemia (ALL) Treated with Risk-Directed Chemotherapy: A Report From the Children's Oncology Group (COG)
Heerema, NA; Carroll, AJ; Borowitz, MJ; Devidas, M; Larson, EC; Loh, M; Mattano, LA; Maloney, K; Raetz, E; Wood, B; Winick, NJ; Hunger, SP; Carroll, WL
2009 NOV 20 ;114(22):1019-1020, Blood
— id: 109992, year: 2009, vol: 114, page: 1019, stat: Journal Article,

Up-Regulation of Genes Involved in Folate Metabolism Characterize Late but Not Early Relapse in Childhood Acute Lymphoblastic Leukemia
Hogan, L; Bhojwani, D; Wang, JH; Morrison, D; Yang, JJ; Zhang, YT; Zavadil, J; Condos, G; Hunger, SP; Willman, CL; Relling, MV; Raetz, E; Carroll, WL
2009 NOV 20 ;114(22):689-690, Blood
— id: 109987, year: 2009, vol: 114, page: 689, stat: Journal Article,

(PLATFORM 302C) ANTISENSE TECHNOLOGY TARGETING AN ANTI-APOPTOTIC GENE IMPROVES LEUKEMIC CELL DEATH IN ALL CELL LINES AND MICE
Hogan, LE; Teachey, DT; Germino, N; Moskowitz, N; Condos, G; Belitskaya-Levy, H; Wang, JH; Bhojwani, D; Horton, TM; Sapra, P; Horak, I; Raetz, E; Grupp, SA; Carroll, W; Morrison, D
2009 JUN ;52(6):695-695, Pediatric blood & cancer
— id: 97794, year: 2009, vol: 52, page: 695, stat: Journal Article,

Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia
Mullighan, CG; Collins-Underwood, JR; Phillips, LAA; Loudin, MG; Liu, W; Zhang, JH; Ma, J; Coustan-Smith, E; Harvey, RC; Willman, CL; Mikhail, FM; Meyer, J; Carroll, AJ; Williams, RT; Cheng, JJ; Heerema, NA; Basso, G; Pession, A; Pui, CH; Raimondi, SC; Hunger, SP; Downing, JR; Carroll, WL; Rabin, KR
2009 NOV ;41(11):1243-U111, Nature genetics
Aneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many individuals with this cancer lack recurring chromosomal alterations. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. We identified the P2RY8-CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8-CRLF2 together with mutated mouse Jak2 resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3 cells overexpressing interleukin-7 receptor alpha. Our findings indicate that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL
— id: 105229, year: 2009, vol: 41, page: 1243, stat: Journal Article,

Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia
Mullighan, Charles G; Su, Xiaoping; Zhang, Jinghui; Radtke, Ina; Phillips, Letha A A; Miller, Christopher B; Ma, Jing; Liu, Wei; Cheng, Cheng; Schulman, Brenda A; Harvey, Richard C; Chen, I-Ming; Clifford, Robert J; Carroll, William L; Reaman, Gregory; Bowman, W Paul; Devidas, Meenakshi; Gerhard, Daniela S; Yang, Wenjian; Relling, Mary V; Shurtleff, Sheila A; Campana, Dario; Borowitz, Michael J; Pui, Ching-Hon; Smith, Malcolm; Hunger, Stephen P; Willman, Cheryl L; Downing, James R
2009 Jan 29;360(5):470-480, New England journal of medicine
BACKGROUND: Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. METHODS: We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL. RESULTS: More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. CONCLUSIONS: Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL
— id: 96132, year: 2009, vol: 360, page: 470, stat: Journal Article,

Gene Expression Profiling in Down Syndrome Acute Lymphoblastic Leukemia Identifies Distinct Profiles Associated with CRLF2 Expression Status
Rabin, KR; Wang, JH; Meyer, J; Loudin, MG; Bhojwani, D; Morrison, D; Heerema, NA; Carroll, AJ; Pession, A; Basso, G; Mullighan, CG; Hunger, SP; Carroll, WL
2009 NOV 20 ;114(22):943-943, Blood
— id: 109990, year: 2009, vol: 114, page: 943, stat: Journal Article,

Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Schultz, KR; Bowman, WP; Aledo, A; Slayton, WB; Sather, H; Devidas, M; Wang, C; Davies, SM; Gaynon, PS; Trigg, M; Rutledge, R; Burden, L; Jorstad, D; Carroll, A; Heerema, NA; Winick, N; Borowitz, MJ; Hunger, SP; Carroll, WL; Camitta, B
2009 NOV 1 ;27(31):5175-5181, Journal of clinical oncology
Purpose Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. Patients and Methods We evaluated whether imatinib (340 mg/m(2)/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph- ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. Results Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% +/- 11% (95% CI, 64% to 90%), more than twice historical controls (35% +/- 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% +/- 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% +/- 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction. Conclusion Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT
— id: 105230, year: 2009, vol: 27, page: 5175, stat: Journal Article,

Germline genomic variants associated with childhood acute lymphoblastic leukemia
Trevino, LR; Yang, WJ; French, D; Hunger, SP; Carroll, WL; Devidas, M; Willman, C; Neale, G; Downing, J; Raimondi, SC; Pui, CH; Evans, WE; Relling, MV
2009 SEP ;41(9):1001-U67, Nature genetics
Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 x 10(-5)) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 x 10(-15), odds ratio (OR) = 1.91; rs10994982, P = 5.7 x 10(-9), OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 x 10(-5), OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n 124 children with ALL; P 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes
— id: 102140, year: 2009, vol: 41, page: 1001, stat: Journal Article,

Patients with Early T-Cell Precursor (ETP) Acute Lymphoblastic Leukemia (ALL) Have High Levels of Minimal Residual Disease (MRD) at the End of induction-A Children's Oncology Group (COG) Study
Wood, B; Winter, S; Dunsmore, K; Raetz, E; Borowitz, MJ; Devidas, M; Winick, NJ; Carroll, WL; Hunger, SP; Loh, ML
2009 NOV 20 ;114(22):9-10, Blood
— id: 109968, year: 2009, vol: 114, page: 9, stat: Journal Article,

Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia
Yang, Jun J; Cheng, Cheng; Yang, Wenjian; Pei, Deqing; Cao, Xueyuan; Fan, Yiping; Pounds, Stanley B; Neale, Geoffrey; Trevino, Lisa R; French, Deborah; Campana, Dario; Downing, James R; Evans, William E; Pui, Ching-Hon; Devidas, Meenakshi; Bowman, W P; Camitta, Bruce M; Willman, Cheryl L; Davies, Stella M; Borowitz, Michael J; Carroll, William L; Hunger, Stephen P; Relling, Mary V
2009 Jan 28;301(4):393-403, JAMA
CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. DESIGN, SETTING, AND PATIENTS: Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. MAIN OUTCOME MEASURES: Minimal residual disease at the end of induction therapy, measured by flow cytometry. RESULTS: There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. CONCLUSION: Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease
— id: 96131, year: 2009, vol: 301, page: 393, stat: Journal Article,

Clinical Outcome of 640 Children with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated Between 1995 and 2005
Arica, M; Schrappe, M; Hunger, S; Carroll, WL; Conter, V; Di Lorenzo, P; Manabe, A; Saba, V; Baruchel, A; Vettenranta, K; Tsuchida, M; Benoit, Y; Pieters, R; Escherich, G; Silverman, LB; Pui, CH; Valsecchi, MG
2008 NOV 16 ;112(11):213-214, Blood
— id: 93285, year: 2008, vol: 112, page: 213, stat: Journal Article,

Evolution of Gene Expression Signatures in Relapsed Childhood Acute Lymphoblastic Leukemia Differs Based on Timing of Relapse
Bhojwani, D; Wang, J; Yang, JJ; Morrison, D; Devidas, M; Raetz, E; Hunger, SP; Relling, MV; Carroll, WL
2008 NOV 16 ;112(11):1149-1149, Blood
— id: 93293, year: 2008, vol: 112, page: 1149, stat: Journal Article,

Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: a Children's Oncology Group Study on behalf of the Dutch Childhood Oncology Group and the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia
Bhojwani, Deepa; Kang, Huining; Menezes, Renee X; Yang, Wenjian; Sather, Harland; Moskowitz, Naomi P; Min, Dong-Joon; Potter, Jeffrey W; Harvey, Richard; Hunger, Stephen P; Seibel, Nita; Raetz, Elizabeth A; Pieters, Rob; Horstmann, Martin A; Relling, Mary V; den Boer, Monique L; Willman, Cheryl L; Carroll, William L
2008 Sep 20;26(27):4376-4384, Journal of clinical oncology
PURPOSE: To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures. PATIENTS AND METHODS: Gene expression profiles were generated from bone marrow blasts at initial diagnosis from a cohort of 99 children with National Cancer Institute-defined high-risk ALL who were treated uniformly on the Children's Oncology Group (COG) 1961 study. For prediction of early response, genes that correlated to marrow status on day 7 were identified on a training set and were validated on a test set. An additional signature was correlated with long-term outcome, and the predictive models were validated on three large, independent patient cohorts. Results We identified a 24-probe set signature that was highly predictive of day 7 marrow status on the test set (P = .0061). Pathways were identified that may play a role in early blast regression. We have also identified a 47-probe set signature (which represents 41 unique genes) that was predictive of long-term outcome in our data set as well as three large independent data sets of patients with childhood ALL who were treated on different protocols. However, we did not find sufficient evidence for the added significance of these genes and the derived predictive models when other known prognostic features, such as age, WBC, and karyotype, were included in a multivariate analysis. CONCLUSION: Genes and pathways that play a role in early blast regression may identify patients who may be at risk for inferior responses to treatment. A fully validated predictive gene expression signature was defined for high-risk ALL that provided insight into the biologic mechanisms of treatment failure
— id: 87810, year: 2008, vol: 26, page: 4376, stat: Journal Article,

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study
Borowitz, Michael J; Devidas, Meenakshi; Hunger, Stephen P; Bowman, W Paul; Carroll, Andrew J; Carroll, William L; Linda, Stephen; Martin, Paul L; Pullen, D Jeanette; Viswanatha, David; Willman, Cheryl L; Winick, Naomi; Camitta, Bruce M
2008 Jun 15;111(12):5477-5485, Blood
Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603
— id: 96133, year: 2008, vol: 111, page: 5477, stat: Journal Article,

"When can I go home?"-seeking ways to lower the burden on patients and families
Carroll, William L; Raetz, Elizabeth A
2008 Sep;51(3):318-319, Pediatric blood & cancer
— id: 80817, year: 2008, vol: 51, page: 318, stat: Journal Article,

Risk-adapted therapy for children with acute lymphoblastic leukemia (ALL): The children's oncology group (COG) approach
Carroll, WL; Hunger, SP; Borowitz, MJ; Bhojwani, D; Willman, CL; Devidas, M; Schultz, K; Loh, ML; Raetz, EA
2008 FEB ;87(1):S42-S47, Annals of hematology
— id: 87145, year: 2008, vol: 87, page: S42, stat: Journal Article,

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research
Eapen, M; Zhang, M-J; Devidas, M; Raetz, E; Barredo, J C; Ritchey, A K; Godder, K; Grupp, S; Lewis, V A; Malloy, K; Carroll, W L; Davies, S M; Camitta, B M
2008 Feb;22(2):281-286, Leukemia
In children with acute lymphoblastic leukemia (ALL) with isolated central nervous system (CNS) relapse and a human leucocyte antigen (HLA)-matched sibling, the optimal treatment after attaining second remission is unknown. We compared outcomes in 149 patients enrolled on chemotherapy trials and 60 HLA-matched sibling transplants, treated in 1990-2000. All patients achieved a second complete remission. Groups were similar, except the chemotherapy recipients were younger at diagnosis, less likely to have T-cell ALL and had longer duration (> or = 18 months) first remission. To adjust for time-to-transplant bias, left-truncated Cox's regression models were constructed. Relapse rates were similar after chemotherapy and transplantation. In both treatment groups, relapse rates were higher in older children (11-17 years; RR 2.81, P=0.002) and shorter first remission (< 18 months; RR 3.89, P<0.001). Treatment-related mortality rates were higher after transplantation (RR 4.28, P=0.001). The 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar after chemotherapy with irradiation and transplantation (66 and 58%, respectively). In the absence of an advantage for one treatment option over another, the data support use of either intensive chemotherapy with irradiation or HLA-matched sibling transplantation with total body irradiation containing conditioning regimen for children with ALL in second remission after an isolated CNS relapse
— id: 135322, year: 2008, vol: 22, page: 281, stat: Journal Article,

Increased Incidence of Osteonecrosis (ON) with a Dexamethasone (DEX) Induction for High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report from the Children's Oncology Group (COG)
Mattano, LA; Nachman, JB; Devidas, M; Winick, N; Raetz, E; Carroll, WL; Whitlock, JA; Hunger, SP; Larsen, EC
2008 NOV 16 ;112(11):333-334, Blood
— id: 93286, year: 2008, vol: 112, page: 333, stat: Journal Article,

Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study
Nguyen, K; Devidas, M; Cheng, SC; La, M; Raetz, EA; Carroll, WL; Winick, NJ; Hunger, SP; Gaynon, PS; Loh, ML
2008 DEC ;22(12):2142-2150, Leukemia
Despite great progress in curing childhood acute lymphoblastic leukemia (ALL), survival after relapse remains poor. We analyzed survival after relapse among 9585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988 and 2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary end point was survival. Patients were subcategorized by the site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0 +/- 1.8%. Standard risk patients who relapsed had improved survival compared with their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10 + years) and the presence of central nervous system disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. It can be noted that there was no difference in survival rates for relapsed patients in earlier vs later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance
— id: 91383, year: 2008, vol: 22, page: 2142, stat: Journal Article,

Biology and treatment of acute lymphoblastic leukemia
Pieters, Rob; Carroll, William L
2008 Feb;55(1):1-20, ix, Pediatric clinics of North America
Acute lymphoblastic leukemia (ALL), the most common type of cancer in children, is a heterogeneous disease in which many genetic lesions result in the development of multiple biologic subtypes. Today, with intensive multiagent chemotherapy, most children who have ALL are cured. The many national or institutional ALL therapy protocols in use tend to stratify patients in a multitude of different ways to tailor treatment to the rate of relapse. This article discusses the factors used in risk stratification and the treatment of pediatric ALL
— id: 96134, year: 2008, vol: 55, page: 1, stat: Journal Article,

Gene Expression Profiling Differentiates Childhood Acute Lymphoblastic Leukemia in Down Syndrome Versus Non-Down Syndrome Patients
Rabin, KR; Wang, JH; Tsimelzon, A; Morrison, D; Gaikwad, AS; Hogan, L; Rye, CL; Hilsenbeck, SG; Devidas, M; Heerema, NA; Carroll, AJ; Basso, G; Carroll, WL; Pession, A; Bhojwani, D
2008 NOV 16 ;112(11):438-439, Blood
— id: 93287, year: 2008, vol: 112, page: 438, stat: Journal Article,

Reinduction platform for children with first marrow relapse in acute lymphoblastic lymphoma
Raetz, Elizabeth A; Borowitz, Michael J; Devidas, Meenakshi; Linda, Stephen B; Hunger, Stephen P; Winick, Naomi J; Camitta, Bruce M; Gaynon, Paul S; Carroll, William L
2008 Aug 20;26(24):3971-3978, Journal of clinical oncology
PURPOSE: Treatment of childhood relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. The goal of the Children's Oncology Group (COG) AALL01P2 study was to develop a safe and active chemotherapy reinduction platform, which could be used to evaluate novel agents in future trials. PATIENTS AND METHODS: One hundred twenty-four patients with ALL and first marrow relapse received three, 35-day blocks of reinduction chemotherapy: 69 with early relapse (ER; < 36 months from initial diagnosis) and 55 with late relapse (LR). Minimal residual disease (MRD) was measured by flow cytometry after each treatment block. RESULTS: Second complete remission (CR2) rates at the end of block 1 in 117 assessable patients were 68% +/- 6% for ER (n = 63) and 96% +/- 3% for LR (n = 54; P < .0001). Five of seven patients with T-cell ALL (T-ALL) failed to achieve CR2. Among patients in CR2, MRD greater than 0.01% was detected at the end of block 1 in 75% +/- 7% of ER (n = 36) versus 51% +/- 8% of LR (n = 43; P = .0375) and 12-month event-free survival was 80% +/- 7% versus 58% +/- 7% in MRD-negative versus positive patients (P < .0005). Blocks 2 and 3 of therapy resulted in reduction of MRD burden in 40 of 56 patients who were MRD positive after block 1. Toxicity was acceptable during all three blocks with five deaths (4%) from infections. CONCLUSION: The AALL01P2 regimen is a tolerable and active reinduction platform, suitable for testing in combination with novel agents in B-precursor ALL. Alternative strategies are needed for T-ALL. Serial MRD measurements were feasible and prognostic of outcome
— id: 82923, year: 2008, vol: 26, page: 3971, stat: Journal Article,

Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group Pilot Study
Raetz, Elizabeth A; Cairo, Mitchell S; Borowitz, Michael J; Blaney, Susan M; Krailo, Mark D; Leil, Tarek A; Reid, Joel M; Goldenberg, David M; Wegener, William A; Carroll, William L; Adamson, Peter C
2008 Aug 1;26(22):3756-3762, Journal of clinical oncology
PURPOSE: To determine the tolerability and serum concentration of epratuzumab, a humanized monoclonal antibody targeting CD22, administered alone and in combination with reinduction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL), and to preliminarily assess tumor targeting and efficacy. PATIENTS AND METHODS: Therapy consisted of a single-agent phase (epratuzumab 360 mg/m(2)/dose intravenously twice weekly x four doses), followed by four weekly doses of epratuzumab in combination with standard reinduction chemotherapy. Morphologic and minimal residual disease (MRD) responses were determined at the end of this 6-week period. Serum concentrations of epratuzumab were determined before and 30 minutes after infusions, and CD22 targeting efficiency was determined by quantifying changes in CD22 expression after epratuzumab administration. RESULTS: Fifteen patients (12 fully assessable for toxicity) with first or later CD22-positive ALL marrow relapse enrolled on the feasibility portion of this study from December 2005 to June 2006. Two dose-limiting toxicities occurred: one grade 4 seizure of unclear etiology and one asymptomatic grade 3 ALT elevation. In all but one patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration, indicating effective targeting of leukemic cells by epratuzumab. Nine patients achieved a complete remission after chemoimmunotherapy, seven of whom were MRD negative. CONCLUSION: Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and acceptably tolerated in children with relapsed CD22-positive ALL. CD22 targeting was efficient, and the majority of patients achieved favorable early responses
— id: 80821, year: 2008, vol: 26, page: 3756, stat: Journal Article,

Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia
Yang, Jun J; Bhojwani, Deepa; Yang, Wenjian; Cai, Xiangjun; Stocco, Gabriele; Crews, Kristine; Wang, Jinhua; Morrison, Debra; Devidas, Meenakshi; Hunger, Stephen P; Willman, Cheryl L; Raetz, Elizabeth A; Pui, Ching-Hon; Evans, William E; Relling, Mary V; Carroll, William L
2008 Nov 15;112(10):4178-4183, Blood
The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we utilized human 500K single-nucleotide polymorphism (SNP) arrays to identify somatic copy number alterations (CNA) in 20 diagnosis/relapse pairs relative to germline. In total, we identified 758 CNAs, 66.4% of which were < 1Mb, and deletions outnumbered amplifications by ~2.5:1. While CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (i.e. absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. Additionally, we noted concordance in global gene expression and DNA copy number changes (P=2.2 x 10(-16)). Finally, relapse-specific focal deletion of MSH6 and consequently reduced gene expression was found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse
— id: 86639, year: 2008, vol: 112, page: 4178, stat: Journal Article,

End points to establish the efficacy of new agents in the treatment of acute leukemia
Appelbaum, Frederick R; Rosenblum, Daniel; Arceci, Robert J; Carroll, William L; Breitfeld, Philip P; Forman, Stephen J; Larson, Richard A; Lee, Stephanie J; Murphy, Sharon B; O'Brien, Susan; Radich, Jerald; Scher, Nancy S; Smith, Franklin O; Stone, Richard M; Tallman, Martin S
2007 Mar 1;109(5):1810-1816, Blood
Federal regulations provide 2 pathways for approval of new agents for the treatment of acute leukemia, regular and accelerated approval. Regular approval requires evidence of clinical benefit, which is generally defined as either prolongation of life or improved quality of life, or an effect on an end point established as a surrogate for clinical benefit. Accelerated approval can be obtained based on demonstration of an effect on a surrogate measure 'reasonably likely' to predict clinical benefit, but requires demonstration of clinical benefit after approval as well. The acute leukemias are a heterogeneous and relatively uncommon group of diseases. The design and execution of prospective randomized clinical trials demonstrating prolongation of life or improved quality of life for patients with these disorders can be difficult and costly and require lengthy follow-up. Thus, the development of novel trial design and inclusion of validated surrogate markers for clinical benefit are needed. To explore some of the issues pertinent to the choice of end points for drug approval in acute leukemia, the Food and Drug Administration invited the American Society of Hematology to participate in the organization and conduct of a joint workshop. In this report, we present the results of that effort
— id: 74584, year: 2007, vol: 109, page: 1810, stat: Journal Article,

Potential of gene expression profiling in the management of childhood acute lymphoblastic leukemia
Bhojwani, Deepa; Moskowitz, Naomi; Raetz, Elizabeth A; Carroll, William L
2007 ;9(3):149-156, Paediatric drugs
Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease. Current treatment approaches are tailored according to the clinical features of the host, genotypic features of the leukemic blast, and early response to therapy. Although these approaches have been successful in dramatically improving outcomes, approximately 20% of children with ALL still relapse and many of these children do not have an identifiable adverse risk factor at presentation. Further insights into the biologic basis of the disease may contribute to novel, rational treatment strategies.Childhood ALL has served as an example for demonstrating the feasibility and potential of high-throughput technologies such as global gene expression or transcript profiling. In the last decade or so, utilization of these techniques has grown exponentially. As the methodology undergoes refinement and validation, it is plausible that microarrays may be used in the routine management of childhood ALL in the next few years. This article discusses the numerous applications to date of gene expression profiling in childhood ALL.Multiple investigators have made it evident that microarrays can be used as a single platform for the accurate classification of ALL into the various cytogenetic subtypes. Additional promising utilities include prediction of early response to therapy, overall outcome, and adverse effects. Identification of patients who are predicted to have an unfavorable outcome may allow for early intervention such as intensification of therapy or avoidance of drugs that are associated with specific secondary effects such as therapy-related acute myelogenous leukemia. Knowledge has been gained into pathways contributing to leukemogenesis and chemoresistance. Therapeutic targets have been identified, some of which are entering clinical trials following validation in additional preclinical models.These newer methods of genome analyses complemented by studies involving the proteome as well as host polymorphisms will have a profound impact on the diagnosis and management of childhood ALL
— id: 73237, year: 2007, vol: 9, page: 149, stat: Journal Article,

Obesity and outcome in pediatric acute lymphoblastic leukemia
Butturini, Anna M; Dorey, Frederick J; Lange, Beverly J; Henry, David W; Gaynon, Paul S; Fu, Cecilia; Franklin, Janet; Siegel, Stuart E; Seibel, Nita L; Rogers, Paul C; Sather, Harland; Trigg, Michael; Bleyer, W Archie; Carroll, William L
2007 May 20;25(15):2063-2069, Journal of clinical oncology
PURPOSE: To evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: We retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Children's Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002. RESULTS: The 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% +/- 2.4% v 77% +/- 0.6% (P = .02) and 26 +/- 2.4 v 20 +/- 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesity's hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients > or = 10 years old at diagnosis; in this subset, obesity's adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients 10 years old, obesity's adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity. CONCLUSION: Obesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL
— id: 74582, year: 2007, vol: 25, page: 2063, stat: Journal Article,

Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)
Schultz, Kirk R; Pullen, D Jeanette; Sather, Harland N; Shuster, Jonathan J; Devidas, Meenakshi; Borowitz, Michael J; Carroll, Andrew J; Heerema, Nyla A; Rubnitz, Jeffrey E; Loh, Mignon L; Raetz, Elizabeth A; Winick, Naomi J; Hunger, Stephen P; Carroll, William L; Gaynon, Paul S; Camitta, Bruce M
2007 Feb 1;109(3):926-935, Blood
The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials
— id: 74586, year: 2007, vol: 109, page: 926, stat: Journal Article,

Genetic studies of a cluster of acute lymphoblastic leukemia cases in Churchill County, Nevada
Steinberg, Karen K; Relling, Mary V; Gallagher, Margaret L; Greene, Christopher N; Rubin, Carol S; French, Deborah; Holmes, Adrianne K; Carroll, William L; Koontz, Deborah A; Sampson, Eric J; Satten, Glen A
2007 Jan;115(1):158-164, Environmental health perspectives
OBJECTIVE: In a study to identify exposures associated with 15 cases of childhood leukemia, we found levels of tungsten, arsenic, and dichlorodiphenyldichloroethylene in participants to be higher than mean values reported in the National Report on Human Exposure to Environmental Chemicals. Because case and comparison families had similar levels of these contaminants, we conducted genetic studies to identify gene polymorphisms that might have made case children more susceptible than comparison children to effects of the exposures. DESIGN: We compared case with comparison children to determine whether differences existed in the frequency of polymorphic genes, including genes that code for enzymes in the folate and purine pathways. We also included discovery of polymorphic forms of genes that code for enzymes that are inhibited by tungsten: xanthine dehydrogenase, sulfite oxidase (SUOXgene), and aldehyde oxidase. PARTICIPANTS: Eleven case children were age- and sex-matched with 42 community comparison children for genetic analyses. Twenty parents of case children also contributed to the analyses. RESULTS: One bilalleleic gene locus in SUOX was significantly associated with either case or comparison status, depending on which alleles the child carried (without adjusting for multiple comparisons). CONCLUSIONS: Although genetic studies did not provide evidence that a common agent or genetic susceptibility factor caused the leukemias, the association between a SUOXgene locus and disease status in the presence of high tungsten and arsenic levels warrants further investigation. RELEVANCE: Although analyses of community clusters of cancer have rarely identified causes, these findings have generated hypotheses to be tested in subsequent studies
— id: 74583, year: 2007, vol: 115, page: 158, stat: Journal Article,

Children with t(12;21)/TEL-AML1-positive acute lymphoblastic leukemia exhibit a distinct germline genomic signature
Trevino, LR; Yang, WJ; Hunger, S; Carroll, WL; Devidas, M; Willman, CL; Downing, J; Evans, WE; Pui, CH; Relling, MV
2007 NOV 16 ;110(11):234A-234A, Blood
— id: 76176, year: 2007, vol: 110, page: 234A, stat: Journal Article,

Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: A pediatric oncology group study
Barredo, JC; Devidas, M; Lauer, SJ; Billett, A; Marymont, M; Pullen, J; Camitta, B; Winick, N; Carroll, W; Ritchey, AK
2006 JUL 1 ;24(19):3142-3149, Journal of clinical oncology
Prognosis and outcome of children with isolated CNS relapse of acute lymphoblastic leukemia (ALL) has depended on duration of first complete remission (CR1). This study intensified systemic therapy by delaying CNS radiation for 12 months and tailored CNS radiation by CR1 duration. Patients and Methods Seventy-six children with first isolated CNS relapse of ALL were treated with systemic chemotherapy that effectively penetrates into the CSF and intrathecal chemotherapy for 12 months. Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CRI of 18 months or more received cranial radiation only (18 Gy), followed by maintenance chemotherapy. Additionally, asymptomatic patients were enrolled in a thiotepa up-front therapeutic window. Results Seventy-four (97.4%) of 76 eligible patients achieved a second remission. Overall 4-year event-free survival (EFS) for the 71 precursor B-cell patients was 70.1% 5.8%. CRI duration and National Cancer Institute (NCI; National Institutes of Health, Bethesda, MID) risk group at initial diagnosis predicted outcome. Patients with CR1 of less than 18 months and 18 months or more had a 4-year EFS of 51.6% 11.3% and 77.7% +/- 6.4% (P=.027), respectively. NCI high-versus standard-risk 4-year EFS was 51.4% +/- 10.8% and 80.2% +/- 6.3% (P =.0018), respectively. A significant difference in EFS between standard risk/CR1 of at least 18 months and both high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups was detected (P=.0068 and .0314, respectively). Response rate to thiotepa was 78%. Most relapses involved the bone marrow, and three second malignancies were reported. Conclusion Twelve months of intensive systemic chemotherapy with reduced dose cranial radiation (18 Gy) is highly effective for children with isolated CNS relapse and CRI of 18 months or more. Novel strategies are needed for patients with CRI of less than 18 months
— id: 66452, year: 2006, vol: 24, page: 3142, stat: Journal Article,

Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study
Bhojwani, Deepa; Kang, Huining; Moskowitz, Naomi P; Min, Dong-Joon; Lee, Hokyung; Potter, Jeffrey W; Davidson, George; Willman, Cheryl L; Borowitz, Michael J; Belitskaya-Levy, Ilana; Hunger, Stephen P; Raetz, Elizabeth A; Carroll, William L
2006 Jul 15;108(2):711-717, Blood
Outcome for children with childhood acute lymphoblastic leukemia (ALL) who relapse is poor. To gain insight into the mechanisms of relapse, we analyzed gene-expression profiles in 35 matched diagnosis/relapse pairs as well as 60 uniformly treated children at relapse using the Affymetrix platform. Matched-pair analyses revealed significant differences in the expression of genes involved in cell-cycle regulation, DNA repair, and apoptosis between diagnostic and early-relapse samples. Many of these pathways have been implicated in tumorigenesis previously and are attractive targets for intervention strategies. In contrast, no common pattern of changes was observed among late-relapse pairs. Early-relapse samples were more likely to be similar to their respective diagnostic sample while we noted greater divergence in gene-expression patterns among late-relapse pairs. Comparison of expression profiles of early- versus late-relapse samples indicated that early-relapse clones were characterized by overexpression of biologic pathways associated with cell-cycle regulation. These results suggest that early-relapse results from the emergence of a related clone, characterized by the up-regulation of genes mediating cell proliferation. In contrast, late relapse appears to be mediated by diverse pathways
— id: 68296, year: 2006, vol: 108, page: 711, stat: Journal Article,

Childhood acute lymphoblastic leukemia in the age of genomics
Carroll, William L; Bhojwani, Deepa; Min, Dong-Joon; Moskowitz, Naomi; Raetz, Elizabeth A
2006 May 1;46(5):570-578, Pediatric blood & cancer
The recent sequencing of the human genome and technical breakthroughs now make it possible to simultaneously determine mRNA expression levels of almost all of the identified genes in the human genome. DNA 'chip' or microarray technology holds great promise for the development of more refined, biologically-based classification systems for childhood ALL, as well as the identification of new targets for novel therapy. To date gene expression profiles have been described that correlate with subtypes of ALL defined by morphology, immunophenotype, cytogenetic alterations, and response to therapy. Mechanistic insights into treatment failure have come from the definition of mRNA signatures that predict in vitro chemoresistance, as well as differences between blasts at relapse and new diagnosis. New bioinformatics tools optimize data mining, but validation of findings is essential since 'over-fitting' the data is a common danger. In the future, genomic analysis will be complemented by evaluation of the cancer proteome
— id: 64130, year: 2006, vol: 46, page: 570, stat: Journal Article,

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research
Eapen, Mary; Raetz, Elizabeth; Zhang, Mei-Jie; Muehlenbein, Catherine; Devidas, Meenakshi; Abshire, Thomas; Billett, Amy; Homans, Alan; Camitta, Bruce; Carroll, William L; Davies, Stella M
2006 Jun 15;107(12):4961-4967, Blood
The best treatment approach for children with B-precursor acute lymphoblastic leukemia (ALL) in second clinical remission (CR) after a marrow relapse is controversial. To address this question, we compared outcomes in 188 patients enrolled in chemotherapy trials and 186 HLA-matched sibling transplants, treated between 1991 and 1997. Groups were similar except that chemotherapy recipients were younger (median age, 5 versus 8 years) and less likely to have combined marrow and extramedullary relapse (19% versus 30%). To adjust for time-to-transplant bias, treatment outcomes were compared using left-truncated Cox regression models. The relative efficacy of chemotherapy and transplantation depended on time from diagnosis to first relapse and the transplant conditioning regimen used. For children with early first relapse (< 36 months), risk of a second relapse was significantly lower after total body irradiation (TBI)-containing transplant regimens (relative risk [RR], 0.49; 95% confidence interval [CI] 0.33-0.71, P < .001) than chemotherapy regimens. In contrast, for children with a late first relapse (> or = 36 months), risks of second relapse were similar after TBI-containing regimens and chemotherapy (RR, 0.92; 95% CI, 0.49-1.70, P = .78). These data support HLA-matched sibling donor transplantation using a TBI-containing regimen in second CR for children with ALL and early relapse
— id: 68297, year: 2006, vol: 107, page: 4961, stat: Journal Article,

Double delayed intensification (DDI) is equivalent to single DI (SDI) in children with national cancer institute (NCI) standard-risk acute lymphoblastic leukemia (SR-ALL) treated on children's cancer group (CCG) clinical trial 1991 (CCG-1991)
Matloub, Y; Angiolillo, A; Bostrom, B; Hunger, SP; Nachman, J; Sather, H; Carroll, WL; Winick, N; Gaynon, PS
2006 NOV 16 ;108(11):47A-48A, Blood
— id: 71380, year: 2006, vol: 108, page: 47A, stat: Journal Article,

Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines
Min, Dong-Joon; Moskowitz, Naomi P; Brownstein, Carrie; Lee, Hokyung; Horton, Terzah M; Carroll, William L
2006 Nov;11(11):1977-1986, Apoptosis
Cancer cell resistance to chemotherapy may be mediated by defects in apoptotic pathways. A prior study showed that in vivo apoptosis of Acute Lymphoblastic Leukemia (ALL) blasts in response to chemotherapy could occur through diverse pathways including both p53-dependent and -independent mechanisms. In this study we investigated the apoptotic response in more detail by using a panel of ALL cell lines that differed in respect to p53 status. Upon exposure to a uniform stimulus, expression of apoptotic proteins, including the effector caspase-3, varied among ALL cell lines partly depending on p53 transcriptional activity and caspase-8 activation. Although the expression and contribution to apoptosis differed among known members of the apoptotic pathway, apoptosis was universally mediated by mitochondrial depolarization. The NFkappaB pathway was activated in response to chemotherapy but NFkappaB inhibition appeared to not influence chemosensitivity. This study further documents the highly variable nature of cell death programs in ALL and provides the foundation for cell death pathway modulation to improve ALL cure rates without increasing chemotherapy-related toxicity
— id: 74585, year: 2006, vol: 11, page: 1977, stat: Journal Article,

Eliminating a gold standard in childhood acute lymphoblastic leukemia?
Raetz, Elizabeth A; Carroll, William L
2006 Sep;47(3):242-244, Pediatric blood & cancer
— id: 68298, year: 2006, vol: 47, page: 242, stat: Journal Article,

Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma
Raetz, Elizabeth A; Perkins, Sherrie L; Bhojwani, Deepa; Smock, Kristi; Philip, Mary; Carroll, William L; Min, Dong-Joon
2006 Aug;47(2):130-140, Pediatric blood & cancer
BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL) and are often thought to represent a spectrum of a single disease. The malignant cells in T-ALL and T-LL are morphologically indistinguishable, and they share the expression of common cell surface antigens and cytogenetic characteristics. However, despite these similarities, differences in the clinical behavior of T-ALL and T-LL are observed. PROCEDURE: We analyzed the gene expression profiles of T-ALL and T-LL samples obtained from Children's Oncology Group (COG) tumor banks using DNA arrays. Immunohistochemistry was also performed to validate the expression of selected targets. RESULTS: Unsupervised hierarchical clustering of all samples showed complete segregation of T-ALL and T-LL into distinct clusters. Next, we identified the top 201 genes that best differentiated T-ALL from T-LL using significance analysis of microarrays (SAM), a supervised statistical approach. Genes representing several functional groups were differentially expressed in T-LL and T-ALL. Prediction analysis of microarrays (PAM) identified a subset of genes, which accurately classified all 19 T-ALL and T-LL samples with an overall misclassification error rate of 0. Immunohistochemical validation of protein expression of selected genes identified by microarray analysis confirmed overexpression of MLL-1 in T-LL tumor cells compared to T-ALL and CD47 in T-ALL tumors cells when compared to T-LL. CONCLUSIONS: Despite significant similarities between the malignant T-cell precursors, clear differences in the gene expression profiles were observed between T-ALL and T-LL implying underlying differences in the biology of the two entities
— id: 68299, year: 2006, vol: 47, page: 130, stat: Journal Article,

Gene expression pathways that distinguish diagnosis and relapse in childhood acute lymphoblastic leukemia
Bhojwani, D; Raetz, E; Moskowitz, N; Lee, H; Sohn, B; Hunger, SP; Carroll, WL
2005 NOV 16 ;106(11):250A-250A, Blood
— id: 61464, year: 2005, vol: 106, page: 250A, stat: Journal Article,

Building better therapy for children with acute lymphoblastic leukemia
Carroll, William L; Raetz, Elizabeth A
2005 Apr;7(4):289-291, Cancer cell
Childhood acute lymphoblastic leukemia is one of the most curable of all human cancers, but new approaches are urgently needed for children who relapse and to avoid severe side effects of curative therapy. Work from the laboratories of Rob Pieters and William Evans, including a paper in this issue of Cancer Cell, has led to the identification of genes whose expression correlates with drug crossresistance and long term outcome. The goal is now to integrate these and other findings using gene expression technology into the care of children with the most common pediatric malignancy
— id: 55998, year: 2005, vol: 7, page: 289, stat: Journal Article,

100 questions & answers about your child's cancer
Carroll, William L; Reisman, Jessica B
Sudbury MA : Jones and Bartlett, 2005,
— id: 1825, year: 2005, vol: , page: , stat: ,

Therapy of low-risk subsets of childhood acute lymphoblastic leukemia: When do we say enough?
Hunger, Stephen P; Winick, Naomi J; Sather, Harland N; Carroll, William L
2005 Dec;45(7):876-880, Pediatric blood & cancer
— id: 57591, year: 2005, vol: 45, page: 876, stat: Journal Article,

Gene signatures predictive of outcome in higher risk childhood acute lymphoblastic leukemia (ALL)
Moskowitz, NP; Bhojwani, D; Kang, H; Min, DJ; Potter, J; Harvey, R; Seibel, NL; Raetz, E; Sather, HN; Hunger, SP; Willman, CL; Carroll, WL
2005 NOV 16 ;106(11):418A-418A, Blood
— id: 61466, year: 2005, vol: 106, page: 418A, stat: Journal Article,

A gene expression classifier for improved risk classification and outcome prediction in pediatric acute lymphoblastic leukemia (ALL)
Willman, CL; Kang, HN; Potter, JW; Harvey, RC; Atlas, SR; Bedrick, E; Helman, P; Veroff, RL; Chen, IM; Carroll, AJ; Ar, K; Xu, YX; Murphy, SB; Bhojwani, D; Moskowitz, N; Carroll, WL; Camitta, B
2005 NOV 16 ;106(11):225A-225A, Blood
— id: 61463, year: 2005, vol: 106, page: 225A, stat: Journal Article,

Racial and ethnic factors in outcomes of children with acute lymphoblastic leukemia - Reply
Carroll, WL
2004 JUN 2 ;291(21):2541-2541, JAMA
— id: 46631, year: 2004, vol: 291, page: 2541, stat: Journal Article,

Autoregulation of the N-myc gene is operative in neuroblastoma and involves histone deacetylase 2
Kim, Marianne K H; Carroll, William L
2004 Nov 1;101(9):2106-2115, Cancer
BACKGROUND: Autoregulation of the myc gene family is a negative feedback mechanism known to occur at high levels of Myc expression. Loss of this mechanism and associated Myc overexpression has been observed in human tumors, thereby contributing to tumorigenesis. The childhood tumor neuroblastoma is characterized by N-myc amplification in aggressive and highly proliferative tumors that occur in a subset of patients. The precise molecular mechanism of autoregulation is unknown, and previous observations indicated that N-myc autoregulation was intact only in single-copy neuroblastoma cell lines. METHODS: Transient reporter assays and trichostatin A (TSA) experiments were performed to evaluate several candidate genes, including Mxi1, c-myc promoter binding protein 1 (MBP-1), Miz, and histone deacetylase 2 (HDAC2), for their involvement in N-myc autoregulation. Mxi1 and HDAC2 were examined further for their expression levels and effects on endogenous N-myc levels. Finally, their recruitments to the N-myc promoter were investigated by chromatin immunoprecipitation (ChIP). RESULTS: The autoregulatory circuit was operative, even in amplified cell lines. Mxi1 consistently showed a modest effect in down-regulating N-myc in transient reporter assays. Overexpression of the c-myc, Mxi1, and mHDAC2 genes resulted in a threefold to fourfold decrease in endogenous N-myc levels. Mxi1 and HDAC2 were up-regulated by N-Myc in an myc-inducible cell line and in N-myc-expressing cell lines. In addition, down-regulation of the N-myc promoter was relieved in the presence of TSA. Increased association of HDAC2 with the autoregulatory region within the N-myc promoter by ChIP was observed upon down-regulation of endogenous N-myc. CONCLUSIONS: The autoregulatory circuit was intact in both amplified and single-copy neuroblastoma cell lines. Furthermore, myc gene autoregulation occurred through histone deacetylation
— id: 57592, year: 2004, vol: 101, page: 2106, stat: Journal Article,

Childhood leukemia--new advances and challenges
Winick, Naomi J; Carroll, William L; Hunger, Stephen P
2004 Aug 5;351(6):601-603, New England journal of medicine
— id: 57593, year: 2004, vol: 351, page: 601, stat: Journal Article,

Race and outcome in childhood acute lymphoblastic leukemia
Carroll, William L
2003 Oct 15;290(15):2061-2063, JAMA
— id: 57594, year: 2003, vol: 290, page: 2061, stat: Journal Article,

Pediatric acute lymphoblastic leukemia
Carroll, William L; Bhojwani, Deepa; Min, Dong-Joon; Raetz, Elizabeth; Relling, Mary; Davies, Stella; Downing, James R; Willman, Cheryl L; Reed, John C
2003 ;50(4):102-131, Hematology (American Society of Hematology. Education Program)
The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically with current therapy resulting in an event free survival exceeding 75% for most patients. However significant challenges remain including developing better methods to predict which patients can be cured with less toxic treatment and which ones will benefit from augmented therapy. In addition, 25% of patients fail therapy and novel treatments that are focused on undermining specifically the leukemic process are needed urgently. In Section I, Dr. Carroll reviews current approaches to risk classification and proposes a system that incorporates well-established clinical parameters, genetic lesions of the blast as well as early response parameters. He then provides an overview of emerging technologies in genomics and proteomics and how they might lead to more rational, biologically based classification systems. In Section II, Drs. Mary Relling and Stella Davies describe emerging findings that relate to host features that influence outcome, the role of inherited germline variation. They highlight technical breakthroughs in assessing germline differences among patients. Polymorphisms of drug metabolizing genes have been shown to influence toxicity and the best example is the gene thiopurine methyltransferase (TPMT) a key enzyme in the metabolism of 6-mercaptopurine. Polymorphisms are associated with decreased activity that is also associated with increased toxicity. The role of polymorphisms in other genes whose products play an important role in drug metabolism as well as cytokine genes are discussed. In Sections III and IV, Drs. James Downing and Cheryl Willman review their findings using gene expression profiling to classify ALL. Both authors outline challenges in applying this methodology to analysis of clinical samples. Dr. Willman describes her laboratory's examination of infant leukemia and precursor B-ALL where unsupervised approaches have led to the identification of inherent biologic groups not predicted by conventional morphologic, immunophenotypic and cytogenetic variables. Dr. Downing describes his results from a pediatric ALL expression database using over 327 diagnostic samples, with 80% of the dataset consisting of samples from patients treated on a single institutional protocol. Seven distinct leukemia subtypes were identified representing known leukemia subtypes including: BCR-ABL, E2A-PBX1, TEL-AML1, rearrangements in the MLL gene, hyperdiploid karyotype (i.e., > 50 chromosomes), and T-ALL as well as a new leukemia subtype. A subset of genes have been identified whose expression appears to be predictive of outcome but independent verification is needed before this type of analysis can be integrated into treatment assignment. Chemotherapeutic agents kill cancer cells by activating apoptosis, or programmed cell death. In Section V, Dr. John Reed describes major apoptotic pathways and the specific role of key proteins in this response. The expression level of some of these proteins, such as BCL2, BAX, and caspase 3, has been shown to be predictive of ultimate outcome in hematopoietic tumors. New therapeutic approaches that modulate the apoptotic pathway are now available and Dr. Reed highlights those that may be applicable to the treatment of childhood ALL
— id: 45386, year: 2003, vol: 50, page: 102, stat: Journal Article,

Identification of genes that are regulated transcriptionally by Myc in childhood tumors
Raetz, Elizabeth A; Kim, Marianne K H; Moos, Philip; Carlson, Marlee; Bruggers, Carol; Hooper, David K; Foot, Laura; Liu, Tong; Seeger, Robert; Carroll, William L
2003 Aug 15;98(4):841-853, Cancer
BACKGROUND: Amplification of the N-myc oncogene is associated with adverse outcomes in the common childhood tumor, neuroblastoma. Because the transforming properties of Myc are related to its ability to modulate gene expression, the authors used cDNA microarrays to identify potential Myc target genes. METHODS: Expression levels of 4608 genes were analyzed in a series of neuroblastoma cell lines. Identical analyses were performed in a panel of medulloblastoma cell lines to identify c-Myc targets and to determine the extent to which N-Myc targets and c-Myc targets were shared. Comparisons were made between cell lines with high levels versus low levels of Myc protein expression. RESULTS: Array analyses yielded 121 genes with increased expression levels (>or= 1.65-fold) and 9 genes with decreased expression levels in N-Myc-expressing versus nonexpressing cell lines. Many of these were newly identified targets of biologic interest. Fifty percent of the N-Myc targets (60 of 121) were mutual c-Myc targets. A significant correlation between the level of N-myc and selected target gene expression was demonstrated independently in 27 neuroblastoma tumor samples and in an N-myc-inducible cell line system. CONCLUSIONS: A number of diverse pathways are modulated by N-Myc in neuroblastoma. Although, overall, there was significant correlation between myc and target transcript expression among cohorts of tumors, great variability in levels of target expression was seen among individual tumor samples, and this biologic heterogeneity in the levels of target gene expression may offer insight into differences in the clinical behavior of neuroblastoma and may prove to be of prognostic significance in the future
— id: 57595, year: 2003, vol: 98, page: 841, stat: Journal Article,

Diversity of the apoptotic response to chemotherapy in childhood leukemia
Liu, T; Raetz, E; Moos, P J; Perkins, S L; Bruggers, C S; Smith, F; Carroll, W L
2002 Feb;16(2):223-232, Leukemia
Apoptosis is the primary mechanism through which most chemotherapeutic agents induce tumor cell death. The purpose of this study was to determine the extent to which blasts from children with leukemia undergo a uniform apoptotic death pathway in vivo. The expression of pro- and anti-apoptotic proteins p53, p21, MDM-2, BCL-2, BCL-X(L), BCL-X(S), and BAX, and caspase-3 activity was determined in circulating blasts collected from the peripheral blood of children with leukemia prior to, and at serial time points following chemotherapy. Culturing blasts ex vivo for 12 h assessed spontaneous apoptosis and the increment induced by chemotherapy. Baseline apoptosis varied between 3% and 29%. Twenty-four hours following chemotherapy the increase in the percentage of cells undergoing apoptosis ranged from <1% to 38%. Eleven of 20 patients who received initial treatment with a p53-dependent drug showed an increase in p53 expression. In these patients, the levels of p53 target genes were also increased. A uniform pattern of BCL-2 family protein expression was not observed and only a minority of samples showed a change that would favor apoptosis. We conclude that that the initial apoptotic response to chemotherapy in children with leukemia is variable involving both p53-dependent and p53-independent pathways
— id: 57599, year: 2002, vol: 16, page: 223, stat: Journal Article,

Identification of gene expression profiles that segregate patients with childhood leukemia
Moos, Philip J; Raetz, Elizabeth A; Carlson, Marlee A; Szabo, Aniko; Smith, Fiona E; Willman, Cheryl; Wei, Qi; Hunger, Stephen P; Carroll, William L
2002 Oct;8(10):3118-3130, Clinical cancer research
To identify genes whose expression correlated with biological features of childhood leukemia, we prospectively analyzed the expression profiles of 4608 genes using cDNA microarrays in 51 freshly processed bone marrow samples from children with acute leukemia, over a 24-month period, at a single institution. Two supervised methods of analysis were used to identify the 20 best discriminating genes between the following cohorts: acute myelogenous leukemia (AML) versus acute lymphoblastic leukemia (ALL); B-lineage versus T-lineage ALL; newly diagnosed B-lineage standard-risk versus high-risk ALL; and B-lineage leukemia harboring the TEL-AML 1 fusion versus patients without a molecularly characterized translocation. These methods identified overlapping sets of genes that segregated patients within described subgroups. Cross-validation demonstrated that the majority of patients could be correctly classified based on these genes alone, and hierarchical clustering grouped patients with similar clinical and biological disease features. The potential for select genes to discriminate patients was validated using real-time PCR in samples that were analyzed by microarray profiling and in other uniformly processed leukemic marrow samples. As expected, microarray technology can successfully segregate patients defined by traditional measures such as immunophenotype and cytogenetic alterations. However, among specific subgroups, this preliminary analysis also suggests that microarrays can identify unanticipated similarities and diversity in individual patients and thus may be useful in augmenting risk-group stratification in the future
— id: 57596, year: 2002, vol: 8, page: 3118, stat: Journal Article,

The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas
Raetz, Elizabeth A; Perkins, Sherrie L; Carlson, Marlee A; Schooler, Kevin P; Carroll, William L; Virshup, David M
2002 Sep;161(3):875-883, American journal of pathology
The majority of pediatric anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) chromosomal translocation that juxtaposes the dimerization domain of nucleophosmin with anaplastic lymphoma kinase (ALK). The nucleophosmin-ALK fusion induces constitutive, ligand-independent activation of the ALK tyrosine kinase leading to aberrant activation of cellular signaling pathways. To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin. Expression of the fusion protein caused a coumermycin-dependent increase in cellular tyrosine phosphorylation and c-Myc immunoreactivity, which was paralleled by a rise in c-myc RNA. To assess the clinical relevance of this observation, c-Myc expression was determined in pediatric ALK-positive and -negative lymphomas. Co-expression of c-Myc and ALK was seen in tumor cells in 15 of 15 (100%) ALK-positive ALCL samples, whereas no expression of either ALK or c-Myc was seen in six of six cases of ALK-negative T-cell lymphoma. C-Myc may be a downstream target of ALK signaling and its expression a defining characteristic of ALK-positive ALCLs
— id: 57597, year: 2002, vol: 161, page: 875, stat: Journal Article,

Variable selection and pattern recognition with gene expression data generated by the microarray technology
Szabo, A; Boucher, K; Carroll, W L; Klebanov, L B; Tsodikov, A D; Yakovlev, A Y
2002 Mar;176(1):71-98, Mathematical biosciences
Lack of adequate statistical methods for the analysis of microarray data remains the most critical deterrent to uncovering the true potential of these promising techniques in basic and translational biological studies. The popular practice of drawing important biological conclusions from just one replicate (slide) should be discouraged. In this paper, we discuss some modern trends in statistical analysis of microarray data with a special focus on statistical classification (pattern recognition) and variable selection. In addressing these issues we consider the utility of some distances between random vectors and their nonparametric estimates obtained from gene expression data. Performance of the proposed distances is tested by computer simulations and analysis of gene expression data on two different types of human leukemia. In experimental settings, the error rate is estimated by cross-validation, while a control sample is generated in computer simulation experiments aimed at testing the proposed gene selection procedures and associated classification rules
— id: 57598, year: 2002, vol: 176, page: 71, stat: Journal Article,

Gene expression profiling. Methods and clinical applications in oncology
Raetz EA; Moos PJ; Szabo A; Carroll WL
2001 Oct;15(5):911-30, ix, Hematology-oncology clinics of North America
The advent of microarray technology undoubtedly will have great impact on the medical field during the next decade. This article discusses different genomic technologies, statistical methods for data analysis, and clinical applications of microarrays. Emphasis is devoted to integration of microarrays into the field of pediatric oncology
— id: 57600, year: 2001, vol: 15, page: 911, stat: Journal Article,

Coexpression of genes involved in apoptosis in central nervous system neoplasms
Bruggers CS; Fults D; Perkins SL; Coffin CM; Carroll WL
1999 Jan-Feb;21(1):19-25, Journal of pediatric hematology/oncology
PURPOSE: Apoptosis plays a crucial role in normal development and mediates tumor response to chemotherapy. This study investigated the pattern of apoptotic gene expression in brain tumor tissue specimens and cell lines. MATERIALS AND METHODS: BCL2, BCLXL, BCLXS, and BAX transcripts were amplified using reverse transcriptase polymerase chain reaction in 7 high-grade gliomas (HGGs), 7 ependymomas, and 6 cell lines (2 glioblastomas, 3 medulloblastomas, and 1 supratentorial-primitive neuroectodermal tumor [PNET]). Immunohistochemical staining for BCL2, BCLX, BAX, and p53 was performed in 7 pediatric low-grade gliomas (LGGs) and 7 pediatric HGGs. RESULTS: Six of seven gliomas, all ependymomas, and all glioblastoma and medulloblastoma cell lines expressed BCLXL and BAX. BCL2 expression was only detected in the supratentorial PNET line PFSK. BCLXS was absent in all tumors. By immunohistochemistry, no glial tumors stained positively for BCL2. Similar BAX and BCLX protein expression was observed in LGG and HGG. Three of five glioblastomas showed significant p53 expression. CONCLUSIONS: Coexpression of proapoptotic and antiapoptotic genes in human brain tumors supports the hypothesis that the relative expression of competing genes determines apoptotic threshold
— id: 57602, year: 1999, vol: 21, page: 19, stat: Journal Article,

A novel intron element operates posttranscriptionally To regulate human N-myc expression
Sivak LE; Pont-Kingdon G; Le K; Mayr G; Tai KF; Stevens BT; Carroll WL
1999 Jan;19(1):155-163, Molecular & cellular biology
Precisely regulated expression of oncogenes and tumor suppressor genes is essential for normal development, and deregulated expression can lead to cancer. The human N-myc gene normally is expressed in only a subset of fetal epithelial tissues, and its expression is extinguished in all adult tissues except transiently in pre-B lymphocytes. The N-myc gene is overexpressed due to genomic amplification in the childhood tumor neuroblastoma. In previous work to investigate mechanisms of regulation of human N-myc gene expression, we observed that N-myc promoter-chloramphemicol acelyltransferase reporter constructs containing sequences 5' to exon 1 were active in all cell types examined, regardless of whether endogenous N-myc RNA was detected. In contrast, inclusion of the first exon and a portion of the first intron allowed expression only in those cell types with detectable endogenous N-myc transcripts. We investigated further the mechanisms by which this tissue-specific control of N-myc expression is achieved. Using nuclear run-on analyses, we determined that the N-myc gene is actively transcribed in all cell types examined, indicating a posttranscriptional mode of regulation. Using a series of N-myc intron 1 deletion constructs, we localized a 116-bp element (tissue-specific element [TSE]) within the first intron that directs tissue-specific N-myc expression. The TSE can function independently to regulate expression of a heterologous promoter-reporter minigene in a cell-specific pattern that mirrors the expression pattern of the endogenous N-myc gene. Surprisingly, the TSE can function in both sense and antisense orientations to regulate gene expression. Our data indicate that the human N-myc TSE functions through a posttranscriptional mechanism to regulate N-myc expression
— id: 57603, year: 1999, vol: 19, page: 155, stat: Journal Article,

Definition of the human N-myc promoter region during development in a transgenic mouse model
Tai KF; Rogers SW; Pont-Kingdon G; Carroll WL
1999 Sep;46(3):255-262, Pediatric research
The N-myc oncogene directs organogenesis, and gene amplification is associated with aggressive forms of neuroblastoma, a common malignant tumor in children. N-myc is expressed in fetal epithelium, and expression decreases markedly postnatally. To localize sequences responsible for directing expression, we have analyzed the human N-myc promoter. We noted previously that N-myc promoter regions 5' to exon 1 directed reporter gene expression in all cell lines, including those without detectable N-myc transcripts. However, when promoter constructs included 3' exon 1 and the 5' portion of intron 1, reporter activity was detected only when there was expression of the endogenous gene. To determine the role of this 'tissue-specific region' in directing expression during development, we generated transgenic mice carrying N-myc promoter lacZ minigenes that contained 5' N-myc promoter elements alone or the promoter linked to the 3' exon 1/5' intron 1 tissue-specific region. Animals lacking the tissue-specific exon 1/intron 1 region showed beta-galactosidase expression in the CNS, but expression was not observed in other organs in which endogenously derived N-myc transcripts were seen. Within the CNS, transgene expression was seen mainly in the olfactory system and was not observed in other areas in which expression of the murine gene has been noted. In contrast, no transgene expression was observed in any of the animals carrying the tissue-specific exon 1/intron 1 region. Thus, sequences that direct expression within the olfactory system were contained within our 5' promoter transgene, whereas sequences that guide the ubiquitous expression of N-myc during organogenesis lie outside the regions studied here. Finally, the exon 1/intron 1 region seems to act in a dominant fashion to repress expression in the CNS from the immediate 5' N-myc promoter
— id: 57601, year: 1999, vol: 46, page: 255, stat: Journal Article,

Somatic hypermutation in T-independent and T-dependent immune responses to Haemophilus influenzae type b polysaccharide
Adderson EE; Shackelford PG; Carroll WL
1998 Dec;89(3):240-246, Clinical immunology & immunopathology
Secondary immune responses to T-independent antigens are characterized by little or no affinity maturation, a phenomenon attributed to limited somatic hypermutation. In the human immune response to Haemophilus influenzae type b capsular polysaccharide, however, there are numerous differences between rearranged heavy chain variable region gene segments and candidate germline genes, irrespective of antigen presentation in a T-independent or T-dependent form. To determine the characteristics of somatic hypermutation in this response, we analyzed rearranged heavy chain variable region segments and associated 3' untranslated JH4-JH5 introns from monoclonal anti-Hib PS antibodies. Mutation of untranslated introns and heavy chain variable segments in both T-independent and T-dependent responses resembles that described in murine and unselected human immune responses. Although mutation is frequent in both T-independent and T-dependent anti-Hib PS responses, there is little evidence of antigen-driven selection, suggesting that ongoing pressure to conserve the variable segment germline configuration limits affinity maturation in this immune response
— id: 57604, year: 1998, vol: 89, page: 240, stat: Journal Article,

Expression of the c-Myc protein in childhood medulloblastoma
Bruggers CS; Tai KF; Murdock T; Sivak L; Le K; Perkins SL; Coffin CM; Carroll WL
1998 Jan-Feb;20(1):18-25, Journal of pediatric hematology/oncology
PURPOSE: The purpose of this study was to determine the incidence of c-Myc protein expression in medulloblastoma/primitive neuroectodermal tumor (MB/PNET) and to identify mechanisms in addition to c-myc gene amplification that lead to increased protein expression. METHODS: We analyzed c-myc gene copy number, mRNA level and protein expression in a panel of MB/PNET cell lines. C-Myc protein levels were assessed in tumor specimens and cell lines using immunohistochemical staining with a c-Myc-specific monoclonal antibody. RESULTS: Southern analysis confirmed c-myc gene amplification in the D425 MED cell line and re-arrangement of one allele in D283 MED, which was analyzed further and appeared to represent a small deletion 3' of exon 3. C-myc transcript levels were dramatically elevated in both lines. Using a c-myc probe, fluorescence in situ hybridization (FISH) showed c-myc present in 3 tandem copies at 8q24 in D283 MED and multiple copies as double minutes in D425 MED. Immunohistochemistry showed c-Myc protein expression in 9 of 10 tumors and all cell lines, regardless of gene amplification status or level of mRNA expression. CONCLUSIONS: c-Myc protein expression is common in MB/PNET tumor specimens and cell lines. Elevated protein levels are observed in the absence of amplification, suggesting that multiple mechanisms of c-myc dysregulation may be involved in MB/PNET. These studies support a role for c-Myc in the development of this common childhood tumor
— id: 57606, year: 1998, vol: 20, page: 18, stat: Journal Article,

The molecular biology of pediatric lymphomas
Goldsby RE; Carroll WL
1998 Jul-Aug;20(4):282-296, Journal of pediatric hematology/oncology
— id: 57605, year: 1998, vol: 20, page: 282, stat: Journal Article,

Autoregulation of the human N-myc oncogene is disrupted in amplified but not single-copy neuroblastoma cell lines
Sivak LE; Tai KF; Smith RS; Dillon PA; Brodeur GM; Carroll WL
1997 Oct 16;15(16):1937-1946, Oncogene
Amplification of the N-myc gene is a significant adverse prognostic factor in neuroblastoma, a common childhood tumor. In non-transformed cells, myc expression is controlled through an autoregulatory circuit, through which elevated Myc protein levels lead to down-regulation of myc transcription. The precise mechanism of myc gene autoregulation is unknown. Loss of c-myc autoregulation has been documented in transformed cells from a number of different lineages, but N-myc autoregulation has not yet been investigated. In neuroblastoma, the increased N-Myc protein produced by amplified tumors would be expected to silence N-myc transcription if the autoregulatory loop were intact. To determine whether N-myc autoregulation is operative in human neuroblastoma, and to localize cis-acting elements which mediate N-myc autosuppression, we transfected a series of N-myc 5' promoter constructs into a panel of human neuroblastoma cell lines carrying one or multiple copies of N-myc. The transfected promoter was equally active in single-copy and amplified lines. Significant promoter activity in the presence of abundant Myc protein in amplified neuroblastoma lines indicates that autoregulation is disabled in this subset of tumors. To investigate whether single-copy lines produce insufficient N-Myc protein to trigger autosuppression yet retain an intact autoregulatory circuit, we transfected neuroblastoma lines with 5' promoter constructs in the presence of a c- or N-myc expression vector. Overexpression of c- or N-Myc resulted in diminution of activity of both the transfected promoter and the endogenous N-myc gene in single-copy, but not amplified lines. Using a series of 5' promoter-deletion minigenes, we localized a cis-acting element required for autoregulation close to the transcription start sites. While the precise mechanism of autosuppression remains unknown, we demonstrated that Myc is incapable of silencing the adenovirus major late promoter (AdMLP) in neuroblastoma cells, indicating that Myc suppression of its own promoter and the AdMLP involve distinct components. These studies provide the first systematic investigation of autoregulation in neuroblastoma, and indicate that single-copy neuroblastoma lines produce insufficient N-Myc protein to activate downstream effector(s) of autosuppression; the autoregulatory circuit is otherwise intact. Amplified lines, in contrast, have lost autoregulation
— id: 57607, year: 1997, vol: 15, page: 1937, stat: Journal Article,