# Aberrant megakaryopoiesis in the myleoproliferative neoplasms

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $131,494

## Abstract

PROJECT SUMMARY
Primary myelofibrosis (PMF) is characterized by myeloproliferation, extramedullary hematopoiesis, bone
marrow fibrosis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleen of patients
are full of atypical megakaryocytes that contribute to fibrosis through the release of cytokines including TGF-β.
Our overarching hypothesis is that abnormal megakaryocytes are key drivers of not only bone marrow fibrosis,
but also other phenotypes of primary myelofibrosis, and that targeting them will ameliorate the disease. In the
first funding period, we identified small molecules that induce maturation and polyploidization of malignant
megakaryocytes in mouse models of PMF as well as primary human patient specimens. Based on this NHLBI-
funded research, we have opened a Phase 1 trial of one of these megakaryocyte polyploidization agents,
Alisertib, in PMF. In this competing renewal, we will probe the molecular nature of the defects in PMF
megakaryocytes, and also determine their necessity and sufficiency in the disease. Our preliminary data show
that expression of the key transcription factor GATA1 is suppressed in the majority of both human and mouse
PMF megakaryocytes and further suggest that this deficiency is due to impaired ribosome function. We also
present the surprising result that expression of JAK2V617F selectively in megakaryocytes is sufficient to cause
polycythemia in vivo. In Aim 1, we will investigate the link between activated JAK/STAT signaling, GATA1, and
ribosome function. In Aim 2 we will study how megakaryocyte expression of JAK2 influences the growth of
other cells and also determine whether megakaryocytes are essential for the disease. This work is innovative
in that we are the first to reveal that there is defect in ribosomes in a megakaryocytic disorder and that
megakaryocyte-selective expression of JAK2V617F leads not only to enhanced megakaryopoiesis, but also to
polycythemia in a cell non-autonomous manner. Our research is significant in that it will shed new light on
megakaryocyte biology and pathogenesis and may aid in the identification of additional new potential therapies
for the MPNs. In addition, our work is also relevant to Diamond Blackfan Anemia, as GATA1 mutations account
for a subset of cases and there appears to be a relationship between ribosomal gene mutations and GATA1
translation. Finally, our research will provide additional insights to support the development of agents that
selectively target megakaryocytes in this disease.

## Key facts

- **NIH application ID:** 10307918
- **Project number:** 7R01HL112792-09
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** John D Crispino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $131,494
- **Award type:** 7
- **Project period:** 2021-04-25 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307918

## Citation

> US National Institutes of Health, RePORTER application 10307918, Aberrant megakaryopoiesis in the myleoproliferative neoplasms (7R01HL112792-09). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10307918. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*