# Identifying and targeting epigenetic vulnerabilities in NOTCH1 driven leukemia

> **NIH NIH R03** · GEORGE WASHINGTON UNIVERSITY · 2020 · $79,750

## Abstract

Project Summary
Leukemias are a heterogeneous group of cancers with various etiology, incidence, and prognosis which
are classified by their lineage (lymphoid and myeloid) and cell maturity. T-cell Acute Lymphoblastic
Leukemia (T-ALL) is an aggressive neoplasm of the bone marrow and accounts for ∼20% of all cases
of adult ALL. Despite improvement in the clinical management and survival (∼85-90%) of childhood
leukemia, the prognosis of adult T-ALL remains poor due to a high incidence of relapse with frequent
central nervous system involvement. Transformation of T-cells involves the cooperative effect of
oncogenes and tumor suppressors, which deregulate the mechanisms controlling normal proliferation,
differentiation, and survival. Activating mutations of NOTCH1, a class I transmembrane receptor critical
for lymphopoiesis, have been implicated in over 50% of T-ALL. The high rate of NOTCH1 mutations
suggest a potential vulnerability for targeted intervention; however, the nature of these mutations have
proven difficult to target. In addition to genetic changes, an emerging research topic in T-ALL is the
identification of chromatin modifying enzymes that cooperate with genetic mutations to cause leukemic
self-renewal and drug resistance. We recently discovered that histone demethylase KDM2B regulates
lymphoid commitment through modulation of NOTCH1 signaling and is required for the oncogenicity of
human T-ALL cell lines. Here, we describe compound mutant mice that express constitutively active
NOTCH1 in lymphoid progenitors in the context of either ablation or overexpression of KDM2B. We
propose to study this histone demethylase (a) in the initiation and maintenance of NOTCH1-driven T-
ALL, and (b) map the transcriptional and epigenetic networks involved in T-cell transformation. Overall,
successful completion of this proposal will shed light into the interplay between NOTCH1 signaling and
epigenetic alterations that drive T-cell transformation, and will uncover new targets for therapeutic
intervention.

## Key facts

- **NIH application ID:** 9831143
- **Project number:** 5R03CA219523-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Alexandros Tzatsos
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,750
- **Award type:** 5
- **Project period:** 2018-12-03 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9831143

## Citation

> US National Institutes of Health, RePORTER application 9831143, Identifying and targeting epigenetic vulnerabilities in NOTCH1 driven leukemia (5R03CA219523-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9831143. Licensed CC0.

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