# Targeting cancer stem cells in JAK2V617F induced neoplasm

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $536,307

## Abstract

Project Summary/Abstract
 We aim to develop a new therapeutic strategy for one major form of JAK2V617F-induced
myeloproliferative neoplasms (MPNs), polycythemia vera (PV), with a focus on targeting PV-initiating cells
(cancer stem cells in PV). A curative therapy for PV is still lacking. The proposed studies are based on our
preliminary finding that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) plays a key role in survival
regulation of PV-initiating cells. The Alox5 pathway is known for producing inflammatory (asthma-causing)
leukotrienes, and an FDA-approved human anti-asthma drug called Singulair (Montelukast) blocks
leukotriene receptor binding to reduce the inflammatory response. We have found that Singulair inhibits the
growth of JAK2-V617F-expressing cells in vitro and in mice. Thus, Singulair could be an effective new agent
for treating PV. We hypothesize that leukotrienes produced in the Alox5-pathway play an essential
role in survival regulation of MPN-initiating cells in PV, and Singulair antagonizes the action of
leukotrienes to act as a potential new therapeutic agent for PV. Testing this hypothesis is of clinical
significance and would benefit: 1) PV patients who have not progressed to acute myeloid leukemia (AML);
2) PV patients who are in clinical remission of AML with residual JAK2V617F-expressing cells and may
relapse with time; 3) PV patients who had bone marrow transplantation for treating AML progressed from
PV but still have residual JAK2V617F-expressing cells; and 4) the individuals who have detectable
JAK2V617F transcripts in myeloid cells but have not developed clinical symptoms of PV. Because the Alox5
pathway is known to produce leukotrienes, one plausible mechanistic explanation of action of Singulair is
that it eradicates PV by blocking receptor binding of leukotriens to PV-initiating cells. We also need to know
the underlying molecular mechanisms by which Singulair inhibits PV-initiating cells and PV development. In
fact, our preliminary studies show that JAK2V617F regulates the Alox5 pathway involving two Alox5
downstream genes, beta-catenin (as a stimulator) and Blk (as a suppressor), and it will be important to
investigate whether Singuliar regulates these two genes in PV-initiating cells. Finally, it is critical to
determine whether Singulair inhibits the growth of human PV-initiating cells. The specific aims are: 1) To
determine whether the survival of PV-initiating cells is dependent on leukotrienes and whether a blockade of
leukotrienes by Singulair reduces their effects on PV-initiating cells; 2) To determine the molecular
mechanisms by which Singulair inhibits PV-initiating cells and PV development; and 3) To determine
whether Singulair blocks the Alox5 pathway in human PV-initiating cells and reduces engraftment of human
PV-initiating cells in immunocompromised mice. Broadly, Singulair is a potential therapeutic agent for solid
tumors as Alox5 is associated with tumorigenesis in the colon, lung, pancr...

## Key facts

- **NIH application ID:** 9865281
- **Project number:** 1R01CA245147-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Shaoguang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,307
- **Award type:** 1
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865281

## Citation

> US National Institutes of Health, RePORTER application 9865281, Targeting cancer stem cells in JAK2V617F induced neoplasm (1R01CA245147-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9865281. Licensed CC0.

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