# Project 2: Defining the role of megakaryocyte abnormalities in the progression of primary myelofibrosis

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $535,067

## Abstract

PROJECT SUMMARY 
Prefibrotic myelofibrosis (PrePMF) was formalized in 2016 by the World Health Organization 
(WHO) as a new early indolent form of MF which frequently progresses to myelofibrosis (MF) as 
well as acute leukemia. Abnormal regulation of megakaryocyte development is a key feature of 
both PrePMF and MF. Under normal conditions, committed megakaryocyte progenitors 
proliferate to a limited extent and then give rise to small numbers of large, polyploid 
differentiated megakaryocytes. However, upon acquisition of mutations in key signaling 
molecules, such as MPL, CALR or JAK2, megakaryocyte progenitors expand and promote 
thrombocytosis in PrePMF and thrombocytopenia/myelofibrosis in MF. Previous studies have 
demonstrated that a deficiency of the critical megakaryocyte transcription factor GATA1 leads a 
MF phenotype in mice and that levels of GATA1 are significantly reduced in the bone marrow of 
MF patients. We hypothesize that the loss of GATA1 in MF leads to an aberrant gene 
expression program which includes increased levels of pro-fibrotic and inflammatory cytokines 
such as TGF-β, LNC2 and IL-8, and that these changes drive the transition from Pre-PMF to MF. 
In our project, we will first perform a detailed assessment of cytokine secretion by PrePMF and 
MF megakaryocytes from animal models and patients and determine if these alterations induce 
aberrant megakaryocyte growth and fibrosis (Aim 1). Then we will assess the specific 
contributions of TGF-β to the cell cycle of normal and MF hematopoietic stem cells (Aim 2). 
Finally, we will use information from Aim 1 and 2, as well as from Projects 1 and 3, to study the 
efficacy of drugs that target the microenvironment, malignant hematopoietic stem cells or 
epigenetic regulators on MF in animal models. This work is innovative in that no one has 
characterized the way that malignant megakaryocytes guide the progression from Pre-PMF, a 
relative benign phase, to MF, the final fatal stage of hematopoietic failure in MPNs. Thanks to 
the interactions with the other projects and cores of this PPG, we are uniquely positioned to 
define the mechanisms by which megakaryocytes affect the transition from PrePMF to PMF and 
the contributions of TGF-β, LCN2 and IL8 to disease. Our work is significant in that it will assist 
Project 4 in prioritizing clinical trials already in the pipeline for MF and lead to new targeted 
therapies for the MPNs.

## Key facts

- **NIH application ID:** 10360650
- **Project number:** 5P01CA108671-14
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Anna Rita F Migliaccio
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,067
- **Award type:** 5
- **Project period:** 2006-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360650

## Citation

> US National Institutes of Health, RePORTER application 10360650, Project 2: Defining the role of megakaryocyte abnormalities in the progression of primary myelofibrosis (5P01CA108671-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10360650. Licensed CC0.

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