# Project 1: Molecular Pathogenesis and Therapy of Myelofibrosis

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $354,021

## Abstract

ABSTRACT 
Patients with the myeloproliferative neoplasms (MPNs) Polycythemia vera (PV), essential thrombocythemia 
(ET), and primary myelofibrosis (PMF) suffer progressive cytopenias, bone marrow fibrosis and/or 
transformation to acute leukemia. The identification of somatic activating mutations in the JAK-STAT pathway 
in the majority of MPN patients led to the clinical development of JAK kinase inhibitors. Although they provide 
important clinical benefit, current JAK inhibitors do not show disease-modifying activity in most patients. In 
addition, recent studies have shown that mutations in the chromatin modifier ASXL1 are associated with 
adverse clinical outcome in PMF. These data underscore the need novel therapeutic approaches for MF 
patients based on mechanistic insight into disease pathogenesis. We propose to investigate the mechanisms 
by which JAK2 and ASXL1 mutations cooperate to induce myeloid transformation, and to investigate novel 
therapeutic approaches in MF. This will include studies which evaluate the impact of concurrent JAK-STAT 
pathway and ASXL1 mutations on MPN pathogenesis, progression and therapeutic resistance to targeted 
therapies. We will also investigate the role of novel therapeutic approaches, specifically type II JAK2 inhibitors 
and combined signaling/epigenetic therapies targeting JAK2 and EZH2 in MF murine models and primary 
patient samples. The studies in this project will leverage novel, genetically accurate murine models coupled 
with detailed studies of primary samples from the MPN-RC sample bank. Most importantly, the studies in this 
project are aimed to credential novel therapeutic approaches which can then be transitioned to the clinic for 
near-term mechanism based clinical trials in this research consortium.

## Key facts

- **NIH application ID:** 10360649
- **Project number:** 5P01CA108671-14
- **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:** 2022
- **Award amount:** $354,021
- **Award type:** 5
- **Project period:** 2006-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360649

## Citation

> US National Institutes of Health, RePORTER application 10360649, Project 1: Molecular Pathogenesis and Therapy of Myelofibrosis (5P01CA108671-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10360649. Licensed CC0.

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