# Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $367,346

## Abstract

Project summary
Acute lymphoblastic leukemia (ALL) represents a heterogeneous collection of diseases with
diverse genetic origins, and it is increasingly apparent that effective treatments must be
customized to the individual molecular features of each patient’s disease. To advance this
paradigm, this application focuses on the epigenetic mechanisms of pathogenesis and response
to targeted therapy in ALL. Studies focus on a distinctive genetic subtype that expresses E2A-
PBX1, a chimeric transcription factor that is the major oncogenic driver in 50% of ALL with
selective activation of the pre-B-cell receptor signaling pathway (pre-BCR+) and response to
tyrosine kinase inhibition in preclinical studies. Although inhibition of activated signaling
pathways is a promising therapeutic strategy in ALL, it is complicated by the development of
resistance through a variety of mechanisms. Among these, primary epigenetic alterations are
recently observed as important underlying pathologic mechanisms that drive the plasticity of the
neoplastic state and therapeutic response. In Aim 1, a high throughput genome-wide “omics”
approach will be used to elucidate the chromatin landscape subordinate to E2A-PBX1 in ALL
cells, correlate the epigenome with the transcriptome, identify mis-regulated target genes, and
define their roles in leukemia pathogenesis. In Aim 2, the kinome identified in preliminary
studies to be dependent on E2A-PBX1 and required for ALL will be further characterized and
interrogated for pathologic roles and therapeutic potential using genetic and pharmacologic
methods. In Aim 3, epigenetic mechanisms of resistance to kinase inhibition identified in
extensive preliminary studies using a functional genomics approach based on ultracomplex
shRNA library screens will be further characterized to prospectively interrogate targeted therapy
response in pre-BCR+ ALL using dasatinib resistance as a model. Identified regulatory factors
and compensatory resistance pathways amenable to molecular therapy with specific inhibitors
targeting chromatin-associated proteins will be evaluated in combination with kinase inhibitors
for synergistic efficacy and resistance amelioration. These studies will further characterize the
dependence of ALL cells on specific epigenetic effectors, define their roles in various
transcriptional and signaling pathways that contribute to ALL pathogenesis, and credential their
prospects as therapeutic targets.

## Key facts

- **NIH application ID:** 9878067
- **Project number:** 5R01CA214888-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MICHAEL L CLEARY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,346
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878067

## Citation

> US National Institutes of Health, RePORTER application 9878067, Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia (5R01CA214888-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878067. Licensed CC0.

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