William L Carroll,MD

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

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]
Website: http://www.med.nyu.edu/biosketch/carrow01/publications

Research Theme(s): Pediatric Leukemia
Keywords: Leukemia; Pediatrics; Genomics; Epigenetics

Research Summary:

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 up or down regulated at relapse. 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. A clinical trial using an anti-sense survivin oligonucleotide in combination with conventional chemotherapy is underway for children with relapsed ALL. Connectivity analysis of the relapse specific signature shows that histone deacetylase inhibition may reverse the signature and restore chemosensitivity. Indeed ongoing preclinical work supports this hypothesis and a clinical trial combining HDACi with DNA methyltransferase inhibition (see below) is being initiated.

Copy number analysis likewise reveals focal amplifications and deletions including copy number loss of IKZF1, EBF-1, BTG-1, 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. IKZF1 deletion is a poor prognostic feature of ALL and preliminary work in our laboratory shows that IKZF1 deletion interferes with an apoptotic response to conventional chemotherapy in blasts. Efforts are underway to examine this process in more detail. Finally we have shown that blasts at relapse are much more hypermethylated than their counterparts at diagnosis and cross platform analysis shows that activation of the WNT and MAP kinase pathways may play roles in chemoresistance.

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 ten patients at diagnosis and relapse (e.g. 20 samples). Our work to date 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. This work is undergoing extensive validation and modeling in preclinical models to determine the precise role of these lesions in mediating drug resistance and relapsed disease.

Selected publications: