# Megakaryocyte erythroid progenitor fate specification

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $480,625

## Abstract

Project Summary
A deeper understanding of the molecular mechanisms regulating hematopoietic lineage specification is critical
for developing improved therapeutics for disorders that affect red blood cell and platelet abnormalities.
Currently, we do not know the mechanisms that influence the fate decisions of the megakaryocyte-eryhtroid
progenitors (MEP) that can differentiate down either the red blood cell or megakaryocyte lineage. The overall
goal of this proposal is to identify the mechanisms by which the lineage fate is determined in these bipotent
progenitors. Progress in determining how bipotent cells become committed has been hampered in part due to
lack of ability to identify and enrich for bipotent cells that are at this critical stage. The Krause laboratory has
recently addressed this barrier to progress by enhancing, and then using, an in vitro functional assay for
individual bipotent MEP to develop improved approaches to enrich for the cells. Our preliminary data using
these MEP strongly support the hypothesis that more rapid cell cycling causes an MEP to become biased
toward the erythroid over the megakaryocytic lineage. These data include 1) single cell RNA deep sequencing
to prove that the enriched cells represent a unique progenitor population that is not fully committed to either of
its potential downstream fates and to provide hypothesis-generating data on potential mechanisms of MEP fat
determination; 2) determination of small molecules that influence fate decisions; 3) validation of an approach to
test knockout of specific genes that affect the fate decision (e.g. MYB); 4) CFSE assessment of changes in
proliferation and accompanying cell fate biases; 5) validation of longterm timelapse microscopy from single
cells to colony formation to assess cell cycle timing and fate determination; and 6) use of a novel in vivo cell
cycle timer reporter. Based on these extensive preliminary data, we propose to: 1) test the hypothesis that cell
cycle speed plays a critical role in the MEP fate decision; 2) dissect the molecular mechanisms underlying the
MEP fate decision; and 3) test the hypothesis that the elevated platelet counts in humans and mice with iron
deficiency anemia are due to a biased MEP fate decision. The results of these studies will contribute to our
understanding of fate regulation of normal hematopoietic progenitor cells in mice and healthy human donors,
and will provide important insights relevant to the pathogenesis of common treatment-refractory hematopoietic
diseases including iron refractory iron deficiency anemia and bone marrow failure. Clinical applications also
include enhancement of our ability to produce RBCs and platelets in vitro for transfusion for anemia and
thrombocytopenia.

## Key facts

- **NIH application ID:** 10001510
- **Project number:** 5R01DK114031-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Diane S Krause
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,625
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001510

## Citation

> US National Institutes of Health, RePORTER application 10001510, Megakaryocyte erythroid progenitor fate specification (5R01DK114031-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10001510. Licensed CC0.

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