# Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $568,895

## Abstract

ABSTRACT
Chronic myelomonocytic leukemia (CMML) is a devastating cancer for which there is currently no effective
therapy. Approximately 20% of CMML cases evolve to acute myelogenous leukemia (AML) soon after their
initial diagnosis, contributing to the poor prognosis of CMML patients (median survival: ~20 months). While
recent sequencing efforts identified numerous genetic mutations in CMML, translating these genomic data
into physiological mechanisms and therapeutics remains very challenging. This challenge arises from the
incomplete genetic/epigenetic landscape of CMML and limitations to mechanistically define genetic
interactions of various mutations. Studies during the prior funding period leveraged our innovative CMML
mouse model induced by endogenous oncogenic Nras (NrasG12D/+). Based on our recent results from this
and its derived models as well as results from whole exome sequencing of patient samples, we hypothesize
that the genetic interaction between oncogenic Ras signaling and mutations in epigenetic regulators forms a
positive feedback loop to further strengthen the signaling network and select for additional mutations in
epigenetic regulators during CMML progression and transformation to AML. Therefore, effective targeting of
oncogenic Ras signaling or simultaneous targeting Ras signaling and aberrant epigenetic landscape could
be promising therapeutic strategies against CMML progression, transformation to AML, and/or AML
progression. As a part of our long-term goal to understand the molecular and cellular mechanisms in tumor
initiation, progression, and malignant transformation, in this application we propose: 1) To determine how
NrasG12D cooperates with mutations in epigenetic regulators to promote CMML development; 2) To
determine whether combined therapies effectively control CMML progression, transformation to AML,
and/or AML progression in vivo. Successful accomplishment of the proposed studies will not only provide
insights into the initiation, progression and transformation of CMML, but may also lead to novel insights into
myeloid diseases with RAS pathway mutations and mutations in epigenetic regulators in general.

## Key facts

- **NIH application ID:** 9863755
- **Project number:** 5R01CA152108-09
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jing Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $568,895
- **Award type:** 5
- **Project period:** 2011-09-02 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9863755

## Citation

> US National Institutes of Health, RePORTER application 9863755, Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML) (5R01CA152108-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9863755. Licensed CC0.

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