William L Carroll, MD

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Julie and Edward J. Minskoff Professor of Pediatrics and Pathology
Director, NYU Cancer Institute NYU-Langone Medical
M.D., 1978 University of California, Irvine, CA

RESEARCH THEMES:
Pediatric Leukemia
KEYWORDS:
Leukemia; Pediatrics; Genomics; Epigenetics

Contact Information

NYU-Langone Medical Center
522 First Avenue, Smilow 12th Floor, Suite 1201
New York, NY 10016
Tel: (212) 263 3019
Fax: (212) 263 9190
E-mail: william.carroll@nyumc.org
[Preferred method of contact: e‐mail]
 


Genetic and epigenetic mechanisms leading to relapse of pediatric Acute Lymphoblastic Leukemia with emphasis on developing new rational therapies.

Our laboratory is focused on developing new approaches to treatment of the most common childhood tumor, acute lymphoblastic leukemia (ALL). While the cure rate for these children has improved markedly over the past four to five decades, ALL remains a leading cause of death in children. We aim to discover the underlying biological pathways that mediate transformation and relapse in order to develop new targeted therapies. To achieve this goal we have used high throughput genomic approaches to describe the genetic and epigenetic evolution of ALL from diagnosis to relapse using a large cohort of paired diagnosis and relapse samples from children enrolled on clinical protocols. We have identified a gene expression signature that predicts relapse as well as a relapse specific gene expression signature where a series of genes are uniquely regulated at relapse. In depth analysis of several genes and pathways stemming from this genomic study has led to the initiation of clinical trials. Survivin is one such gene whose expression rises dramatically at relapse in a majority of patients. Survivin functions as an anti-apoptotic protein and plays a role in cell division. Based on our preclinical results, a clinical trial using an anti-sense survivin oligonucleotide in combination with conventional chemotherapy was performed with children with relapsed ALL. Connectivity analysis of the relapse specific signature showed that histone deacetylase inhibition may reverse the signature and restore chemosensitivity. Indeed preclinical work supports this hypothesis and a clinical trial combining HDACi with DNA methyltransferase inhibition has been initiated. Preliminary results from this trial are encouraging.

Copy number analysis likewise reveals focal amplifications and deletions including copy number loss of IKZF1, EBF-1, BTG-1, TBLXR1, NR3C1 and MSH6 at relapse. Loss of NR3C1 (steroid receptor) and BTG-1 (transcriptional activator of steroid receptor) explain the loss of response to the most common chemotherapeutic agents in ALL but these deletions occur in a minority of patients. Recent work from the lab now indicates that multiple genetic events (including TBLXR1 deletion) all converge on disabling the transcriptional complex on the promoters of steroid responsive genes. These findings have broad implications for the treatment of many hematological malignancies. Efforts are underway to examine this process in more detail. Finally cross platform analysis shows that activation of the WNT and MAP kinase pathways play key roles in chemoresistance and we have used molecularly targeted inhibitors in preclinical models demonstrating the potential of such approaches in clinical trials

The introduction of next generation sequencing has revolutionized cancer genomics and we have taken advantage of this technology by using RNAseq to characterize the expressed genetic repertoire of patients at diagnosis and relapse (e.g. 20 samples). Our work indicates that clonal selection leads to an outgrowth of a dominant clone characterized by mutations in both known as well as novel cancer related genes. We have shown that a significant number of patients have relapse-specific mutations in NT5C2, a gene that plays a fundamental role in resistance to purine analogues that are the cornerstone of maintenance therapy for childhood ALL. Lab members are using sensitive next generation sequencing strategies to use the detection of low, but emerging, levels of NT5C2 as a biomarker of impending relapse.

 Efforts are underway to use ChIPseq to provide a complete portrait of those epigenetic changes that result in drug resistance as well as the identification of long non-coding RNAs.

All of the above studies have led to the discovery of the underlying genetic and cellular events to lead to treatment failure in the most common childhood tumor. Importantly these results have been used to develop novel treatment approaches.

Selected Publications: 
  • Ramezani-Rad P, Geng H, Hurtz C, Chan LN, Chen Z, Jumaa H, Melnick A, Paietta E, Carroll WL, Willman CL, Lefebvre V, Müschen M. SOX4 enables oncogenic survivalsignals in acute lymphoblastic leukemia. BLOOD. 2013 Jan 3;121(1):148-55. PMCID: 23152540
  • Loh ML, Zhang J, Harvey RC, Roberts K, Payne-Turner D, Kang H, Wu G, Chen X, Becksfort J, Edmonson M, Buetow KH, Carroll WL, Chen IM, Wood B, Borowitz MJ, Devidas M, Gerhard DS, Bowman P, Larsen E, Winick N, Raetz E, Smith M, Downing JR, Willman CL, Mullighan CG, Hunger SP. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project. BLOOD. 2013 Jan 17;121(3):485-8. PMID: 23212523
  • Meyer JA, Wang J, Hogan LE, Yang JJ, Dandekar S, Patel JP, Tang Z, Zumbo P, Li S, Zavadil J, Levine RL, Cardozo T, Hunger SP, Raetz EA, Evans WE, Morrison DJ, Mason CE, Carroll WL.  Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.  Nat Genet. 2013 Mar;45(3):290-4. PMID: 23377183
  • Carroll WL. Safety in numbers: hyperdiploidy and prognosis. BLOOD. 2013 Mar 28;121(13):2374-6. PMID: 23538228
  • Xu H, Yang W, Perez-Andreu V, Devidas M, Fan Y, Cheng C, Pei D, Scheet P, Burchard EG, Eng C, Huntsman S, Torgerson DG, Dean M, Winick NJ, Martin PL, Camitta BM, Bowman WP, Willman CL, Carroll WL, Mullighan CG, Bhojwani D, Hunger SP, Pui CH, Evans WE, Relling MV, Loh ML, Yang JJ. Novel Susceptibility Variants at 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethnically Diverse Populations. J Natl Cancer Inst. 2013 May 15;105(10):733-42. PMID: 23512250
  • Hunger SP, Loh ML, Whitlock JA, Winick NJ, Carroll WL, Devidas M, Raetz EA; COG Acute Lymphoblastic Leukemia Committee. Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia. Pediatric Blood Cancer. 2013 Jun;60(6):957-63. PMID: 23255467
  • Salzer WL, Asselin B, Supko JG, Devidas M, Kaiser NA, Plourde P, Winick NJ, Reaman GH, Raetz E, Carroll WL, Hunger SP. Erwinia Asparaginase Achieves Therapeutic Activity after PEG-asparaginase Allergy: A Report from the Children’s Oncology Group. BLOOD. 2013 Jul 25; 122(4):507-14. PMID: 23741010
  • Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, Ng C, Titz B, Hurtz C, Sadiyah MF, Nowak D, Thoennissen GB, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A, Müschen M. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nature Medicine. 2013 Aug;19(8):1014-22. PMID: 23852341
  • Heerema NA, Carroll AJ, Devidas M, Loh ML, Borowitz MJ, Gastier-Foster JM, Larsen EC, Mattano LA, Maloney KW, Willman CL, Wood B, Winick NJ, Carroll WL, Hunger SP, Raetz EA. Intrachromosomal Amplification of Chromosome 21 Is Associated with Inferior Outcomes in Children with Acute Lymphoblastic Leukemia on Contemporary Standard Risk Children’s Oncology Group Studies, A Report from the Children’s Oncology Group.  J Clin Oncol. 2013 Sep 20;31(27):3397-3402. PMID: 5492441
  • Raetz EA, Morrison D, Romanos-Sirakis E, Gaynon P, Sposto R, Bhojwani D, Bostrom B, Brown P, Eckroth E, Cassar J, Malvar J, Buchbinder A, Carroll WL.  A Phase I Study of EZN-3042, a Novel Survivin Messenger Ribonucleic Acid (mRNA) Antagonist, Administered in Combination with Chemotherapy in Children with Relapsed Acute Lymphoblastic Leukemia (ALL):  A Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium. J Pediatr Hematol Oncol. 2013 Oct 31. PMID: 24276047
  • Roy S, Di Cello F, Kowalski J, Hristov AC, Tsai HL, Bhojwani D, Meyer JA, Carroll WL, Belton A, Resar LM. HMGA1 overexpression correlates with relapse in childhood B-lineage acute lymphoblastic leukemia. Leuk Lymphoma. 2013 Nov;54(11):2565-7. PMID: 23472968
  • Perez-Andreu V, Roberts KG, Harvey RC, Yang W, Cheng C, Pei D, Xu H, Gastier-Foster J, E S, Lim JY, Chen IM, Fan Y, Devidas M, Borowitz MJ, Smith C, Neale G, Burchard EG, Torgerson DG, Klussmann FA, Villagran CR, Winick NJ, Camitta BM, Raetz E, Wood B, Yue F, Carroll WL, Larsen E, Bowman WP, Loh ML, Dean M, Bhojwani D, Pui CH, Evans WE, Relling MV, Hunger SP, Willman CL, Mullighan CG, Yang JJ. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013 Dec;45(12):1494-8. PMID: 24141364
  • Patel JD, Krilov L, Adams S, Aghajanian C, Basch E, Brose MS, Carroll WL, de Lima M, Gilbert MR, Kris MG, Marshall JL, Masters GA, O'Day SJ, Polite B, Schwartz GK, Sharma S, Thompson I, Vogelzang NJ, Roth BJ. Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol. 2014 Jan 10;32(2):129-60. PMID: 24327669
  • Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Zheng HW, Davies SM, Gaynon PS, Trigg M, Rutledge R, Jorstad D, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B. Long term follow-up of imatinib in pediatric philadelphia chromosome-positive acute lymphoblastic leukemia: children's oncology group study AALL0031. Leukemia. 2014 Jan 20. PMID: 24441288
  • Chatterton Z, Morenos L, Mechinaud F, Ashley DM , Craig JM , Sexton-Oates A, Halemba M, Parkinson-Bates M, Ng J, Morrison D, Carroll WL, Saffery R, Wong NC. Epigenetic deregulation in pediatric Acute Lymphoblastic Leukemia.  Epigenetics. 2014 Mar 1;9(3):459-67. PMID: 24394348
  • Raetz EA, Carroll WL. Refining prognosis in BCR-ABL1-positive ALL. BLOOD. 2014 Mar 13;123(11):1626-7. PMID: 24627518
  • Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas J, Borowitz MJ, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase III COG/PBMTC trial. BLOOD. 2014 Mar 27;123(13):2017-25. PMID: 24497539
  • Schultz KR, Devidas M, Bowman WP, Aledo A, Slayton WB, Sather H, Zheng HW, Davies SM, Gaynon PS, Trigg M, Rutledge R, Jorstad D, Carroll AJ, Heerema N, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B. Philadelphia chromosome negative very high risk acute lymphoblastic leukemia (ALL) in children and adolescents: results from children's oncology group (COG) study AALL0031.Leukemia. 2014 Apr;28(4):964-7. PMID: 24434862
  • Myers RM, Balsamo L, Lu X, Devidas, M, Hunger SP, Carroll WL, Winick NJ, Maloney KW, and Kadan-Lottick NS. A Prospective Study of Anxiety, Depression, and Behavioral Changes in the First Year after Diagnosis of Childhood Acute Lymphoblastic Leukemia. Cancer. 2014 May 1;120(9):1417-25. PMID: 24473774
  • Vitanza NA, Zaky W, Blum R, Meyer JA, Wang J, Bhatla T, Morrison DJ, Raetz EA, Carroll WL. Ikaros Deletions in BCR-ABL1-Negative Childhood Acute Lymphoblastic Leukemia are Associated with a Distinct Gene Expression Signature but Do Not Result in Intrinsic Chemoresistance. (Accepted-In Press) Pediatric Blood & Cancer. 2014. PMID: 24976218
  • Bhatla T, Jones CL, Meyer JA, Vitanza NV, Raetz EA, Carroll WL. The Biology of relapsed leukemia: Opportunities for Therapeutic interventions. (Accepted-In Press) Journal of Pediatric Hematology-Oncology. 2014 Aug;36(6):413-8. PMID: 24942023
  • Jones CL, Bhatla T, Wang J, Bourgeois W, Bitterman D, Raetz E, Morrison D, Teachey D, Garabedian M, Carroll WL. Loss of TBLXR1 disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance in childhood B-Lymphoblastic leukemia model. (Accepted-In Press) J. Biol. Chem. 2014 Jul 25;289(30):20502-20515. PMID: 24895125
  • Dandekar S, Romanos-Sirakis E, Pais F, Bhatla T, Jones C, Bourgeois W, Hunger SP, Raetz E, Hermiston M, Dasgupta R, Morrison D, Carroll WL. Wnt Inhibition Leads to Improved Chemosensitivity in Pediatric Acute Lymphoblastic Leukemia. (Accepted-In Press) Br J Haem. 2014. PMID: 24995804