# Project 1: Molecular Pathogenesis and Therapy of Myelofibrosis

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $430,560

## Abstract

PROJECT 1 ABSTRACT
PI: Ross Levine, MD
Primary myelofibrosis (MF) and progression of polycythemia vera (PV) and essential thrombocytosis (ET) to MF
represent the most pressing clinical needs of patients with myeloproliferative neoplasms (MPNs), given that MF
patients develop progressive cytopenias, splenomegaly, bone marrow fibrosis, disabling systemic symptoms
and/or transformation to a treatment refractory form of acute leukemia, termed MPN-blast phase. The
identification of somatic activating mutations involving the JAK2, MPL and CALR genes in most MPN/MF patients
has underscored the role of constitutive JAK-STAT signaling in MF pathogenesis and has led to the clinical
development of JAK2 inhibitors as the standard of care for MF patients. Clinical experience with currently
available JAK2 inhibitors has shown that these agents can reduce cytokine production and attenuate MPN
symptoms but are not capable of inducing either pathologic or molecular responses in most patients. Our recent
work has uncovered a role for key epigenetic and inflammatory pathways in MF pathogenesis, which cooperate
with activated JAK-STAT signaling to drive clinical progression and adverse outcomes in MF patients. These
newly identified epigenetic and inflammatory pathways provide mechanistic insights into MPN disease
pathogenesis and have the potential to serve as targets for the development of novel MF therapeutic approaches.
We propose to investigate the role of aberrant epigenetic/inflammatory effector pathways in MF pathogenesis
and to identify novel therapeutic targets which cooperate with JAK2 inhibition to increase therapeutic efficacy.
The studies in this project will leverage novel, genetically accurate murine models of the most common MPN
genotypes, coupled with detailed genomic, epigenomic, and therapeutic studies of primary samples from the
MPN-RC Tissue Bank (Core B). Most importantly, the studies in this project are aimed to develop and credential
novel therapeutic approaches that can then be transitioned to the clinic for mechanism based clinical trials in
collaboration with Project 4 and the entire MPN-RC.

## Key facts

- **NIH application ID:** 10866391
- **Project number:** 5P01CA108671-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ross L Levine
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $430,560
- **Award type:** 5
- **Project period:** 2006-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866391

## Citation

> US National Institutes of Health, RePORTER application 10866391, Project 1: Molecular Pathogenesis and Therapy of Myelofibrosis (5P01CA108671-16). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10866391. Licensed CC0.

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