# Target the Dusp1 in Jak2 dependent myeloproliferative neoplasm (MPN) for curative treatment

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $178,205

## Abstract

Despite the impressive response to tyrosine kinase inhibitor (TKI) therapy in the clinic as an anti-cancer
treatment, it is not curative. Even the most potent kinase inhibitors are ineffective against a small
population of cancer cells, which are insensitive to treatment; manifesting as minimal residual disease
(MRD). Likewise, myeloproliferative disorders treated with Jak2 inhibitors show intrinsic resistance to
TKI treatment . Failure eradicate the persistent cells them leads to post-therapy relapse. Therapeutic
response to TKI is mediated by oncogene-addiction; however, the molecular mechanisms governing
TKI-induced cell death in the context of oncogene-addiction is not clearly understood. We find that
MAPK phosphatase, Dusp1, is a critical mediator of oncogene-addiction in MPD driven by mutations in
JAK2, MPL and CSF3R. Overexpression of Dusp1 in MPDs abrogates oncogene addiction and ablates
TKI response. Both genetic and pharmacological inhibition of Dusp1 is synthetic lethal to Jak2-V761F
and CSF3R-T618I driven MPDs. The proposed research will address the sensitivity of murine-model
of MPD leukemia initiating cells and primary patient specimens to disrupting Dusp1 activity alone and
in the context of TKI therapy. In addition, we propose to develop specific and potent Dusp1 inhibitor
using structure function studies for clinical application. Our results should accelerate development of
a curative therapy for MPDs.

## Key facts

- **NIH application ID:** 10799650
- **Project number:** 5R21CA280723-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Mohammad Azam
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $178,205
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799650

## Citation

> US National Institutes of Health, RePORTER application 10799650, Target the Dusp1 in Jak2 dependent myeloproliferative neoplasm (MPN) for curative treatment (5R21CA280723-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10799650. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*