The outcome for children with relapsed acute lymphoblastic leukemia is dismal especially if relapse occurs while on therapy. While the cure rate for newly diagnosed ALL continues to climb there has been no improvement in outcome for relapsed ALL (survival 20% to 45% depending on interval from diagnosis). Relapsed ALL is one of the most common cancer diagnosis in children making relapsed ALL a leading cause of cancer mortality. Thus the discovery of the biological pathways that mediate drug resistance and relapse is a top priority. Over the last funding cycle we have used matched diagnosis and relapse samples from patients enrolled on Children?s Oncology Group (COG) clinical protocols to discover unique relapse-specific somatic lesions that indicate the clonal outgrowth of the relapsed clone(s). We have identified a number of lesions (TBL1XR1 deletions and NT5C2 mutations) and/or activation of biological pathways (Wnt and MAP kinase) that have been validated in preclinical models to result in resistance to one class of agents (e.g. glucocorticoids or purine nucleosides) and pan-resistance (e.g. MEK2 activation). Our work has led to two clinical trials with an additional one in the planning stages. Our results have also indicated that the epigenome has a considerable impact in shaping the resistant phenotype. A fundamental gap in the extensive characterization of the relapsed genome we have completed to date is insight into shifts in promoter and enhancer activation mediated by mutations in gene regulatory regions and/or mutations in epigenetic readers/writers. Given the explosion of evidence that implicates the epigenome in cancer initiation and progression as well as many new agents in clinical trials that modulate epigenetic pathways our proposal is timely. We propose to map major shifts in the histone code (promoters and enhancers) and mutations in regulatory regions between diagnosis and relapse by using ChIP seq/ATAC seq on paired samples already characterized for gene expression (arrays or RNAseq), DNA methylation, copy number and next generation sequencing (Aim1). We will discover the roles and long range interactions of dynamic enhancers and super-enhancers shared by the majority of patients by chromosome capture (Aim 2). Finally we will validate the role of genes and pathways identified in Aims 1 and 2 in a variety of preclinical models. Our ultimate goal is to complete a comprehensive genomic and epigenomic portrait of clonal evolution in a common hematological malignancy and to use this information to structure novel therapeutic approaches to the prevention and treatment of relapse.

Public Health Relevance

Relapsed acute lymphoblastic leukemia (ALL) is one of the most common cancer diagnoses and a leading cause of mortality in children with cancer. While the outcome for newly diagnosed ALL is excellent (> 90% event free survival), the outcome for relapsed ALL is dismal. In the last reporting cycle we discovered a number of biological pathways that lead to drug resistance and relapse. This work led to two clinical trials with a third one in the planning stages. In the current application we propose to study the role of the epigenome in causing drug resistance. Our experiments involve the use of clinical samples from patients so that bona fide drivers of relapse can be identified. Our ability to directly target the biological pathways that lead to drug resistance holds great promise for novel prevention and treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140729-10
Application #
9981483
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kondapaka, Sudhir B
Project Start
2010-07-01
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Snetkova, Valentina; Skok, Jane A (2018) Enhancer talk. Epigenomics 10:483-498
Pierro, Joanna; Hogan, Laura E; Bhatla, Teena et al. (2017) New targeted therapies for relapsed pediatric acute lymphoblastic leukemia. Expert Rev Anticancer Ther 17:725-736
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Walsh, Kyle M; de Smith, Adam J; Hansen, Helen M et al. (2015) A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. Cancer Res 75:4884-94

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