# ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $473,190

## Abstract

Project Summary
Despite intense efforts, the long-term cure rates of patients with acute myeloid leukemia are inadequate.
Resistance to chemotherapy is prevalent, and targets for molecular therapies are only beginning to be defined.
For example, mutation of genes encoding transcription factors and epigenetic regulators cause most subtypes
of AML, but their molecular pathophysiology and pharmacologic accessibility remain poorly defined. We have
now found that leukemogenic gene expression in AML requires distinct molecular interactions between the
pioneer transcription factor MYB and its coactivator CBP. Remarkably, peptidomimetic inhibitors of MYB
transcriptional coactivation exhibit potent anti-leukemia activity in most molecular subtypes of AML while sparing
healthy cells. The central hypothesis of this proposal is that defining and blocking the molecular mechanisms of
aberrant transcriptional coactivation in AML will lead directly to improved therapies for patients. Aim 1 will define
the molecular mechanisms of aberrant activation of leukemic MYB transcription factor complexes that control
oncogenic gene expression. Aim 2 will pursue the preliminary evidence that peptidomimetic and targeted small
molecule inhibitors can be used to dismantle leukemic transcriptional complexes in vivo and develop effective
therapeutic strategies using accurate genetic and patient-derived preclinical mouse models. Successful
completion of this project is expected to yield essential molecular mechanisms and effective therapies of aberrant
transcription factors and gene control in AML, thus providing essential insights into a fundamental problem that
remains poorly understood. This should have broad and lasting significance for understanding and treating
refractory leukemias in particular and human cancer generally.

## Key facts

- **NIH application ID:** 10894239
- **Project number:** 5R01CA204396-09
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alex Kentsis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $473,190
- **Award type:** 5
- **Project period:** 2016-08-22 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894239

## Citation

> US National Institutes of Health, RePORTER application 10894239, ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA (5R01CA204396-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10894239. Licensed CC0.

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