# RON kinase as a novel therapeutic target in myeloproliferative neoplasms

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $46,036

## Abstract

Abstract
The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs), including polycythemia vera
(PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are clonal hematopoietic stem cell
disorders characterized by the proliferation of one or more myeloid lineage compartments. The driver mutations
of MPNs, namely activating mutations in either Janus Kinase 2 (JAK2), thrombopoietin receptor (MPL), or
calreticulin (CALR), function to upregulate JAK/STAT signaling. During disease progression, MPN patients
experience increased pro-inflammatory cytokine secretion, leading to remodeling of the bone marrow
microenvironment and subsequent fibrosis. Currently, the only curative treatment for MPNs is stem cell
transplantation, but most patients are poor candidates due to age or comorbidities. The JAK inhibitor ruxolitinib
is an approved targeted therapy for MPN patients and has shown promise in its ability to reduce splenomegaly
and the cytokine storm observed in patients. However, JAK inhibitors alone are not sufficient to reduce bone
marrow fibrosis or to eliminate the JAK2-mutated clone. Furthermore, JAK inhibitor persistence, or reactivation
of JAK/STAT signaling upon chronic JAK inhibitor treatment, has been observed in both MPN mouse models
and MPN patients. Therefore, there is an urgent need for new treatment options in MPN. The tyrosine kinase
RON is a member of the MET kinase family, and signaling through RON promotes activation of downstream
signals, including pAkt, pErk, and pSTAT3. RON signaling has well characterized roles in erythroblast
proliferation and pro-inflammatory cytokine production. Specifically, the constitutively active short-form RON
(sfRON) isoform is necessary for Friend virus-induced erythroleukemia in mice via signaling through STAT3. In
addition, it was shown that the canonical full-length RON (flRON) isoform is phosphorylated by JAK2 to stimulate
erythroblast proliferation. However, the role of RON in MPN pathogenesis is currently unknown. Preliminary data
from our lab has shown that pharmacological inhibition of RON with the ALK/MET/RON/ROS1 inhibitor crizotinib
inhibits colony formation and JAK/STAT signaling in both patient MPN cells and JAK2-mutated cell lines.
Furthermore, we demonstrated that shRNA knockdown of both flRON and sfRON isoforms in JAK2-mutated cell
lines phenocopies the inhibitory effects of crizotinib. We also found that RON isoform phosphorylation is
enhanced in JAK inhibitor persistent cells, suggesting that RON may potentiate the JAK2 persistence phenotype
in response to JAK inhibitors. Therefore, we hypothesize that RON is a novel mediator of JAK/STAT signaling
in MPNs, and that inhibiting signaling through RON will have therapeutic value in MPN patients. We propose to
examine the roles of RON signaling in MPN disease progression and initiation using MPN mouse models. We
also aim to determine the therapeutic window of targeting RON kinase in MPN by examining its role in th...

## Key facts

- **NIH application ID:** 10074131
- **Project number:** 5F31CA247172-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Lindsay Gurska
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10074131

## Citation

> US National Institutes of Health, RePORTER application 10074131, RON kinase as a novel therapeutic target in myeloproliferative neoplasms (5F31CA247172-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10074131. Licensed CC0.

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