# Role of Hedgehog Signaling in JAK2V617F Associated Myelofibrosis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $425,000

## Abstract

Myelofibrosis (MF) is the deadliest of the various myeloproliferative neoplasms (MPN) that affect
approximately 150,000 people in the United States. MPN are characterized by abnormal
proliferation of one or more of the blood lineages, bone marrow fibrosis, splenomegaly, and
progression to acute myeloid leukemia. The identification of recurrent mutations in these
patients, the most common being the JAK2V617F mutation found in 95% of polycythemia vera
(PV) and 65% of primary MF (PMF) patients, suggests a common molecular pathogenesis
centered on aberrant JAK/STAT signaling; however, JAK inhibitors alone offer only modest
clinical benefit, without cure. Combinations of JAK inhibitors with other inhibitors of oncogenic
pathways such as AKT, MEK/ERK, mTOR, or Hedgehog (Hh), show greater efficacy then JAK
inhibitors alone, suggesting that a complex signaling network drives MPN. During my K08
award period, we have demonstrated that: 1) JAK2V617F transgenic mice show increased
sonicHh (Shh) ligand expression and activation of Smoothened (Smo)/Hh signaling 2)
Treatment with the Hh/Smo inhibitor, PF-04449913 (PF-913, glasdegib), reduces the
splenomegaly, cytokine production, marrow fibrosis and JAK2V617F allele burden 3)
JAK2V617F transgenic tissues show increased MAPK and NFKB signaling as well as increased
TGF-B levels, which decrease with Smo inhibition 4) JAK2V617F mutant cells cause Hh ligand
dependent activation of Hh target genes and TGF-B/SMAD2 signaling in stromal cells.
Therefore, we hypothesize that Hedgehog signaling is essential for JAK2V617F driven
diseases and represents and important therapeutic target. The aims of this study are to
determine how JAK2V617F leads to Hh pathway activation and delineate the autocrine vs
paracrine effects of abnormal Hh signaling in the bone marrow microenvironment. We will focus
on understanding how TGF-B mediates fibrosis and alters the host immune response to MPN.
This study will make use of a breakthrough imaging technique known as Imaging Mass
Cytometry, to characterize with 40+ parameters the paracrine signaling events and immune
response that drives the fibrosis reaction. Understanding the interaction between mutant JAK
signaling and hedgehog signaling has implications beyond MPN, as abnormal JAK/STAT and
Hedgehog signaling have been implicated in numerous cancers as well as in non-cancerous
conditions such as autoimmune diseases, graft verses host disease, inflammation and liver
cirrhosis.

## Key facts

- **NIH application ID:** 9988348
- **Project number:** 5R01HL138414-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Akil Merchant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988348

## Citation

> US National Institutes of Health, RePORTER application 9988348, Role of Hedgehog Signaling in JAK2V617F Associated Myelofibrosis (5R01HL138414-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988348. Licensed CC0.

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