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

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $385,932

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic myelomonocytic leukemia (CMML) is a devastating cancer with an urgent and unmet need for effective
therapies (median survival: ~28 months). Approximately 30% of CMML cases evolve to acute myeloid leukemia
(AML) soon after their initial diagnosis, contributing to the poor prognosis of CMML patients. During the prior
funding period, we collaborated with the International MDS/MPN Consortium and demonstrated that concurrent
NRAS and ASXL1 mutations define a population of CMML patients with shorter leukemia-free survival than those
with ASXL1 mutations only. Based on our human data, we characterized NrasG12D/+; Asxl1-/- (NA) mice that model
CMML patients with concurrent NRAS and ASXL1 mutations. NA mice developed CMML with accelerated
progression and in ~50% of these mice CMML transformed to AML (secondary AML, sAML). NA leukemia cells
exhibited hyperactivation of MEK/ERK signaling and increased global level of H3K27Ac, a histone mark bound
by bromodomain and extra-terminal domain (BET) proteins for gene transcriptional activation. Upregulation of
AP-1 transcription factors (TFs) mediated the overexpression of PD-L1 and CD86, two inhibitory immune
checkpoint ligands, and helped establish a suppressive immune microenvironment in NA-sAML recipients.
Combined inhibition of MEK and pan-BET proteins led to downregulation of AP-1 TF expression, partial
mitigation of the suppressive immune microenvironment, enhancement of CD8 T cell cytotoxicity, and prolonged
survival in NA-sAML mice. Based on our preliminary results, we hypothesize that Asxl1-/- and oncogenic Nras
cooperate to accelerate CMML and promote its transformation to AML via reprogramming the immune
microenvironment, which includes but may not limit to T cells. Moreover, immunomodulatory agents may further
improve the therapeutic benefits of combine MEK and BET inhibition through establishing durable anti-leukemia
activities in immune cells. In this renewal application, we propose the following two aims to test our hypothesis:
1) To identify the molecular and cellular mechanisms underlying the dysregulation of immune microenvironment
in in NA mice; and 2) determine whether immunomodulatory agents further improve the therapeutic effects of
combined MEK and BET inhibition in NA mice. Together, our proposed studies will not only provide fundamental
perspectives on disease mechanisms but also test hypotheses that could potentially lead directly to potent and
efficacious novel therapies for treating CMML and transformed AML.

## Key facts

- **NIH application ID:** 10828857
- **Project number:** 5R01CA152108-12
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jing Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,932
- **Award type:** 5
- **Project period:** 2011-09-02 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828857

## Citation

> US National Institutes of Health, RePORTER application 10828857, Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML) (5R01CA152108-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10828857. Licensed CC0.

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