# MLL Family Histone Methyltransferases in Myeloid Leukemia

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $415,663

## Abstract

PROJECT SUMMARY
Despite some remarkable advances in treating certain types of cancer, the nature of mutations
and heterogeneity of acute myeloid leukemia (AML) have made this cancer challenging to treat
successfully. Genomic data have suggested many new therapeutic targets, but even successful
molecular inhibition does not always translate to effective therapy, justifying a broader
understanding of mechanisms and pathways altered in AML. Our recent studies illuminated a
novel pathway by which the endogenous MLL1 and MLL2 histone methyltransferases contribute
to leukemogenesis driven by MLL fusion oncoproteins. In MLL-AF9 or MLL-AF6-driven AML, we
found that the endogenous MLL2 histone methyltranferase played a major role in sustaining
several coordinated pathways that enhance leukemia survival and proliferation. Although MLL1
did not contribute on its own to leukemogenesis, it collaborated with MLL2 in regulating critical
AML survival/proliferation pathways affecting NFκB, integrin β3 and IL-3 signaling. Given the
widespread reliance on all three of these pathways for AML survival/proliferation, we propose to
test the role and downstream pathways regulated by MLL1 and MLL2 in a variety of genetically
defined AML animal models, as well as human leukemia lines and primary samples.
Specifically, our proposal aims to 1) determine whether loss of MLL1/MLL2 or both affects AML
driven by a variety of genetically-defined murine AML models, 2) identify MLL1/MLL2 regulated
pathways in human AML cells along with the domains within MLL2 that contribute regulating
these pathways, and 3) define the transcriptome perturbations, epigenomic states, and effect of
both Mll1 and Mll2 knockout in MLL-AF9-driven AML and determine the mechanism by which
they collaborate to support AML survival. These experiments will identify epigenetic
vulnerabilities that may be particular to certain cytogenetic subtypes of AML or may be broadly
relevant.

## Key facts

- **NIH application ID:** 10169375
- **Project number:** 5R01CA224436-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Patricia Ernst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,663
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169375

## Citation

> US National Institutes of Health, RePORTER application 10169375, MLL Family Histone Methyltransferases in Myeloid Leukemia (5R01CA224436-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169375. Licensed CC0.

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