# Mechanism and therapeutic opportunities of targeting the Tudor domain

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $485,717

## 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 Tudor domain focused CRISPR screen in MLL-r leukemia identified
SGF29 as a novel vulnerability in MLL-r leukemia. The objective of this application is to determine the critical
epigenetic mechanisms that mediate the availability of KAT2A/B to maintain H3K9ac and oncogene expression
in MLL-r leukemia. Our central hypothesis is that SGF29, an H3K4me3 reader protein, mediates recruitment
of KAT2A/B to maintain histone H3K9ac and MYC oncogenic program in MLL-r leukemia. We will dissect the
SGF29-mediated epigenetic mechanisms (Aim 1) and investigate the efficacy of SGF29 targeting (alone or in
combination with DOT1L inhibition) as a novel therapy in MLL-r leukemia (Aim 2).
 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 pocket and drug 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:** 10746121
- **Project number:** 5R01CA278050-02
- **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:** 2024
- **Award amount:** $485,717
- **Award type:** 5
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746121

## Citation

> US National Institutes of Health, RePORTER application 10746121, Mechanism and therapeutic opportunities of targeting the Tudor domain (5R01CA278050-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10746121. Licensed CC0.

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