# Function and targeting of a stable transcription factor complex in leukemia

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $387,731

## Abstract

PROJECT SUMMARY
Development is controlled by the timely expression and function of transcription factors that regulate gene
expression and determine cell fate and function. Leukemia is often driven by chromosomal translocations that
result in the production of novel transcription factors, produced by the abnormal fusion of two separate gene
products. In acute myelogenous leukemia (AML), the most common such fusion is the t(8;21)-derived AML1-
ETO (AE), which drives leukemia by co-opting additional normal cellular transcription factors that are critical for
blood stem cell self-renewal and proliferation, thereby trapping the cells in a proliferative immature state that is
the basis of leukemia. It has proved difficult to inhibit transcription factor functions pharmacologically, leading
us to look for essential AE cofactors that are more tractable drug targets. Our goal is to combine different
experimental approaches to decipher the mechanisms of gene regulation in AML, including identification of
new players in different hierarchies of regulation that will reveal new opportunities for therapeutics.
 In recent studies, we identified an AE-associated transcription factor/cofactor complex (AETFC) and
pinpointed a novel interaction surface between AE and E proteins that is critical for AETFC function and
leukemogenesis. Most importantly, we showed in mouse models that disruption of this interaction severely
reduces AE oncogenicity. In addition, we also identified JMJD1C as a novel coactivator for AETFC. JMJD1C is
of special interest in that it is a histone 3 lysine 9 demethylase with an enzymatic activity pocket that can
ultimately be targeted by small molecules. Notably, our studies have also shown that JMJD1C is critical for
survival not only of t(8;21) cells, but also several different types of AML cells, suggesting its potential role as a
general coactivator for shared key transcriptional factors, providing another opportunity for therapeutic
development through inhibiting TF-cofactor interaction.
 Based on our published work and preliminary studies, we propose to continue and expand our original
proposed studies in the following aspects. First, we will systematically dissect newly indicated sub-complexes
of AETFC and determine how they guide coactivators and corepressors to important target genes (Aim 1).
Second, we will detail the molecular mechanisms underlying the pan-JMJD1C dependency of different types of
leukemia (Aim 2). We will employ several complementary approaches that include: (i) cell-free systems
reconstituted with purified factors and DNA/chromatin templates, to reveal direct cofactor effects and
mechanisms; (ii) leukemic cell-based assays to monitor dynamic changes upon introduction of mutants or
deletion of components of TF networks; (iii) genome-wide analyses that include ATAC-seq, ChIP-seq and
RNA-seq. Third, we will develop/employ new mouse models for t(8;21) leukemia to validate newly identified
players/interactions in AML (A...

## Key facts

- **NIH application ID:** 9836612
- **Project number:** 5R01CA163086-08
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** ROBERT G ROEDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,731
- **Award type:** 5
- **Project period:** 2011-09-14 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836612

## Citation

> US National Institutes of Health, RePORTER application 9836612, Function and targeting of a stable transcription factor complex in leukemia (5R01CA163086-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9836612. Licensed CC0.

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