# Mechanism of Therapy in high-risk AML

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $488,415

## Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that, despite being treatable with well-
defined chemotherapy regimens, is ultimately fatal in over half of all cases categorized as high-risk AML.
Mutations in MLL, FLT3, DNMT3A and P53 are associated with high-risk AML. Even targeted FLT3 anti kinase
therapy, which constitutes 30 % of AML, failed to engender durable response in this group of AML. Co-operative
oncogenic signaling” was attributed to poor therapeutic outcome, but lacks mechanistic understanding. Based
on our recent publication and new preliminary data, we found that co-operative oncogenic signaling converges
on c-FOS and DUSP1, which results in an increased apoptotic threshold in cancer cells and confers drug
resistance. Thus, genetic or pharmacologic inhibition of c-FOS and DUSP1 sensitizes cancer cells to
chemotherapy (Kesarwani, et. al. Nature Medicine 2017). We show greater expression of c-FOS and DUSP1
in high-risk AML patients, but not in low risk-AML patients. Both genetic and chemical inhibition of c-FOS and
DUSP1 results in increased drug sensitivity to both TKI and conventional chemotherapeutic drugs in a model
of high-risk AML (FLT3ITD+MLLAF9). Thus, we hypothesize that co-operative oncogenic signaling in AML
induces the expression of c-FOS and DUSP1 resulting to drug resistance and disease relapse due to elevated
apoptotic threshold. In Aim 1, we will determine whether c-FOS and DUSP1 are necessary and sufficient for
transformation in a most frequent, aggressive, and fatal AML driven by FLT3ITD+DNMT3Amut+NPM1C and
FLT3ITD+P53mut mutations. We will examine the cellular basis of c-FOS and DUSP1 dependency in the high-
risk AML mouse models and primary patient samples by genetic deletion and pharmacological inhibition of c-
FOS and DUSP1. Next, we propose experiments to understand the mechanistic basis for how co-operative
oncogenic signaling via c-FOS and DUSP1 contributes to transformation and treatment failure in AML, with the
goal for novel treatment strategies. Based on our preliminary data, we hypothesize that c-FOS and DUSP1
signaling converges upon oncogenically-activated enhancers mediated by specific AP-1 transcriptional
complexes. In the presence of c-FOS and DUSP1, AP-1 complexes consist of c-FOS-JUN, which mediate
oncogenically-active enhancers, while in the absence of c-FOS and DUSP1, Jun family homodimers (JUN-
JUNB, JUNB-JUND, JUN-JUND) predominate which are unable to support the leukemic cell state. In Aim 2,
we will molecularly link c-FOS-JUN AP-1 and DUSP1 activity to global enhancer chromatin dynamics.
Moreover, we will exploit chromatin-embedded target-gene-reporter alleles to provide a detailed analysis of
functionally-relevant downstream genes at a single-cell level in high-risk AML. The proposed work is expected
to delineate the necessity of c-FOS and DUSP1 signaling in high-risk AML, as well as to provide deep
molecular insight into the mechanisms underlying leukemic transformati...

## Key facts

- **NIH application ID:** 10072745
- **Project number:** 1R01CA250516-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Mohammad Azam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $488,415
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072745

## Citation

> US National Institutes of Health, RePORTER application 10072745, Mechanism of Therapy in high-risk AML (1R01CA250516-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072745. Licensed CC0.

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