# Project 2: Defining the Role of Megakaryocyte Abnormalities in the Progression of Primary Myelofibrosis

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $442,007

## Abstract

PROJECT 2 ABSTRACT
PIs: John Crispino, PhD; Anna Rita Migliaccio, PhD
Myelofibrosis (MF), caused by mutations in JAK2, MPL, and CALR, progress from a pre-fibrotic stage where
patients have minimal symptoms to a more advanced fibrotic state which is associated with an increasing
symptom burden, progressive splenomegaly, cytopenias and marrow fibrosis. MF disease progression is
characterized by the accumulation of atypical megakaryocytes that express low levels of the critical transcription
factor GATA1 and elevated levels of TGF-β. MF evolves to acute myeloid leukemia (MPN blast phase, MPN-
BP) in nearly 20% of patients. The goal of project 2 is to understand the events that contribute to disease
progression by focusing on megakaryocytes and the factors that they secrete, such as TGF-β and IL-13. Based
on our prior research, we hypothesize that changes in the megakaryocytic lineage substantially contribute to key
features of MF progression, including bone marrow fibrosis, the predominance of MF hematopoietic stem cells
and the impaired function of wild-type hematopoietic stem cells. We further hypothesize that alterations in p53
activity contribute to both the inhibition of normal hematopoiesis and the progression of MF to MPN-BP. In this
project, we will: 1) Investigate the changes in the megakaryocyte lineage that contribute to the MF progression;
2) Identify the contributions of IL-13 and TGF-β to MF progression; and 3) Evaluate and target the contributions
of HIF-1 alpha pathway activation and p53 inhibition driving MF leukemia progression. Our research interacts
with Projects 1 and 3 through our work on cytokines and the role of p53 in MF progression, and with Project 4
through both bench to beside and bedside to bench exchanges of information, with the ultimate goal of bringing
new treatments to MF patients. Our work will also require integration with each of the MPN-RC cores. Drs.
Crispino and Migliaccio have a longstanding history of collaboration, particularly dealing with the role of GATA1
in megakaryopoiesis, and will leverage their complementary expertise to achieve the goals of this project.

## Key facts

- **NIH application ID:** 10866396
- **Project number:** 5P01CA108671-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** John D Crispino
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,007
- **Award type:** 5
- **Project period:** 2006-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866396

## Citation

> US National Institutes of Health, RePORTER application 10866396, Project 2: Defining the Role of Megakaryocyte Abnormalities in the Progression of Primary Myelofibrosis (5P01CA108671-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10866396. Licensed CC0.

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