# Targeting DOT1L for Degradation in MLL-rearranged Leukemia

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $404,076

## Abstract

Project Summary/Abstract
Despite marked progress in the rate of cure among patients with acute leukemia, chromosomal translocations
involving the mixed lineage leukemia gene (MLL1) give rise to highly aggressive acute leukemias associated
with poor clinical outcomes for pediatric and adult patients. Current treatment options are of limited effectiveness;
thus, there is a pressing need for new therapies for this disease. Genetic studies have demonstrated that the
histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged (MLL-r)
leukemia in model systems. Likewise, work from the previous funding cycle clearly defined a role for DOT1L
inhibition in MLL-r leukemia through characterization of a potent, specific DOT1L inhibitor, EPZ-5676
(pinometostat), that has remarkably selective anti-proliferative and pro-apoptotic effects on MLL-rearranged
cells. As pinometostat has progressed through Phase I clinical trials, responses and subsequent relapses imply
the development of acquired resistance to the inhibitor. In this proposal, we seek to understand the biological
underpinnings of DOT1L inhibitor resistance and develop a novel class of small molecule DOT1L degraders to
overcome resistance. In Specific Aim 1, we seek to understand the mechanisms of resistance through detailed
studies of chromatin structure and gene expression following the development of acquired resistance to DOT1L
inhibitor therapy. We will also investigate the non-enzymatic role of DOT1L in MLL-r leukemia and define
dependencies acquired in the resistant state. In Specific Aim 2, we will lead a chemistry and chemical biology
campaign and develop an assay platform for the identification and optimization of the first small molecule
degraders of endogenous DOT1L protein. In Specific Aim 3, we will utilize our cell culture and patient-derived
xenograft models of MLL-r leukemia to explore the impact of DOT1L degradation on gene expression and tumor
progression while driving hit-to-lead optimization of DOT1L degraders that can prompt clinical investigation. We
will also test pharmacological hypotheses regarding combinatorial drug action with DOT1L degraders in
predictive human models of MLL-r leukemia. We expect these aims to bring new more efficacious, less toxic
therapies to children and adults diagnosed with this devastating disease.

## Key facts

- **NIH application ID:** 10169367
- **Project number:** 5R01CA176745-10
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** SCOTT A ARMSTRONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,076
- **Award type:** 5
- **Project period:** 2012-09-25 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169367

## Citation

> US National Institutes of Health, RePORTER application 10169367, Targeting DOT1L for Degradation in MLL-rearranged Leukemia (5R01CA176745-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10169367. Licensed CC0.

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