# Role of BAZ2A in MLL-r leukemia and therapeutic response

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $395,738

## Abstract

PROJECT SUMMARY/ABSTRACT
 MLL-rearranged (MLL-r) leukemias account for 5-10% of human acute leukemia and is associated with
poor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the MLL-r
leukemias emphasize the need for novel regimens. Recent cancer epigenetics studies discovered a
central role for the histone H3 lysine 79 (H3K79) methyltransferase DOT1L in MLL-r leukemogenesis.
Important clinical responses have been noted with DOT1L inhibitor treatment as a single agent, however,
it is expected that combination treatments will be necessary.
 Our preliminary studies based on a DOT1L-inhibitor sensitization screen in MLL-r leukemia have identified
suppression of BAZ2A significantly increases the anti-leukemic activity of the DOT1L inhibitor. The objective
of this application is to determine the critical epigenetic mechanisms that mediate the availability of SIRT1 to
suppress oncogene expression in MLL-r leukemia. Our central hypothesis is that BAZ2A, a chromatin
remodeling protein of rDNA loci, mediates redistribution of SIRT1 for histone deacetylation and silencing of
MLL-r/DOT1L-driven oncogene. We will dissect the BAZ2A/SIRT1 chromatin targeting mechanisms (Aim 1),
investigate the efficacy of DOT1L and BAZ2A combination therapies (Aim 2), and validate a novel saturation
CRISPR protein scan technology for de novo discovery of the functional elements in DOT1L and BAZ2A
(Aim 3).
 This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiple
components of an epigenetic network to efficiently suppress the cancer programs, and (2) it establishes a
brand new genetic screen approach for a sub-protein level functional domain discovery. The impact of this
research will be of significance because (1) it immediately provides novel therapeutic opportunities
against the difficult-to-treat MLL-r leukemias, and (2) it will help identify novel functional elements in
epigenetic regulators for future pharmaceutical targeting.

## Key facts

- **NIH application ID:** 9851842
- **Project number:** 5R01CA236626-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Chun-Wei David Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,738
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851842

## Citation

> US National Institutes of Health, RePORTER application 9851842, Role of BAZ2A in MLL-r leukemia and therapeutic response (5R01CA236626-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851842. Licensed CC0.

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