# Defining IKZF1/IKAROS as an oncogene and therapeutic target in MLL-r AML

> **NIH NIH F32** · DANA-FARBER CANCER INST · 2022 · $72,302

## Abstract

PROJECT SUMMARY
Chromosomal rearrangements involving the KMT2A/Mixed Lineage Leukemia gene (MLL-r) drive the
development and sustained growth of an aggressive form of Acute Myeloid Leukemia (AML). Small molecule
inhibitors of the DOTL1 methyltransferase and MENIN effectively suppress MLL-fusion driven oncogenic gene
expression, however, early clinical studies indicate that resistance will limit clinical utility and highlights an urgent
need for effective combination therapies to improve patient outcomes. Here a functional genomic screening was
undertaken to elucidate resistance mechanisms and synthetic lethal dependencies during treatment with
inhibitors of either MENIN or DOT1L and identified IKZF1/IKAROS as a putative therapeutic target to improve
the efficacy of these drugs; implicating an important role for IKAROS in maintaining the MLL-r oncogenic
transcriptional program. The immunomodulatory (IMiD) drugs, including Lenalidomide, drive degradation of
IKAROS, providing an immediate route to implementing a novel combination therapy with MENIN and DOT1L
inhibitors. Preliminary data suggests that the combination therapy of MENIN inhibition and an IMiD compound
results in synergistic killing of MLL-r AML cell lines.
This proposal aims to (1) characterize the function of IKAROS within the transcriptional program of MLL-r AML
and (2) evaluate IKAROS as a novel therapeutic target in MLL-r AML and characterize the synergistic effect of
the combination MENIN inhibitor/IMiD treatment as it relates to pathways of IKAROS degradation. The use of a
combination of genetic, interactomic, proteomic, mouse models and compound-induced targeted protein
degradation approaches will enable an understanding of the oncogenic contribution of IKAROS and a
mechanistic understanding of the effectiveness of combination treatments. This work will capitalize on expertise
in the biology of MLL-r AML and collaborative work on IMiD compound development and optimization to establish
new effective combination therapies for MLL-r AML. This work will build upon and improve the burgeoning field
of therapeutic uses of targeted protein degraders. The worked described here will continue to develop my
scientific skill set and is in line with my career goals of dissecting mechanisms of protein regulation in leukemia
using cutting edge technologies from multiple disciplines. To that end, a comprehensive training program has
been developed to maximize the potential to become an independent investigator with a unique approach toward
protein science research in the context of disease.

## Key facts

- **NIH application ID:** 10407467
- **Project number:** 5F32CA250240-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Jevon Cutler
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,302
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407467

## Citation

> US National Institutes of Health, RePORTER application 10407467, Defining IKZF1/IKAROS as an oncogene and therapeutic target in MLL-r AML (5F32CA250240-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10407467. Licensed CC0.

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