# Synergistic role of signaling and epigenetics in leukemic transformation

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $1,028,400

## Abstract

Project Summary
Genetic and functional data have demonstrated the importance of somatic mutations in signaling effectors and
in epigenetic modifiers in the pathogenesis of myeloproliferative neoplasms (MPN) and acute myeloid leukemia
(AML). However, the mechanisms by which these two classes of leukemia disease alleles cooperate to induce
transformation, and how coordinate mutations in signaling pathways and in epigenetic regulators affect the
response to targeted therapy, has not been fully elucidated. Here we propose to investigate how mutations in
signaling effectors cooperate with mutations in epigenetic regulators to induce myeloid transformation, and
how these mutations influence the response to targeted therapies including the development of therapeutic
resistance. We will then extend our studies to investigate whether combination therapeutic approaches can
achieve increased efficacy in models of myeloproliferative neoplasms (MPN) and acute myeloid leukemia
(AML). The long-term goals of this proposal are to characterize novel mechanisms by which oncogenic disease
alleles cooperate to induce leukemogenesis, and to credential novel combination strategies that can be
investigated in the clinical context. We will investigate this using a combination of novel, genetically accurate
animal models, epigenomic studies in murine models and patient samples, and preclinical therapeutic studies
aimed at rational design of combination therapeutic strategies. Our studies have a mechanistic focus, but are
aimed to rapidly translate these insights to the clinical context.

## Key facts

- **NIH application ID:** 9841907
- **Project number:** 5R35CA197594-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ross L Levine
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,028,400
- **Award type:** 5
- **Project period:** 2017-01-17 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841907

## Citation

> US National Institutes of Health, RePORTER application 9841907, Synergistic role of signaling and epigenetics in leukemic transformation (5R35CA197594-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841907. Licensed CC0.

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