# Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $405,000

## Abstract

PROJECT SUMMARY
Erythropoietin (Epo) and its receptor EpoR are primary regulators of erythropoiesis.
Normal Epo levels support basal erythropoiesis. In anemia, blood loss, or hypoxia, Epo
levels rise, initiating signaling pathways to expand erythroid progenitors, increasing red
cell production during the erythropoietic stress response. In published work, we showed
that the constitutively active JAK2 mutant JAK2(V617F), found in myeloproliferative
neoplasms, needs to associate with the EpoR to transmit oncogenic signaling in
erythroid progenitors to drive erythrocytosis. While EpoR signaling in more differentiated
erythroid precursors has been extensively studied, EpoR signaling in early progenitors,
which controls stress erythropoiesis and erythrocytosis, has not been elucidated.
In preliminary studies, we show that JAK2(V617F) oncogenic signaling requires the
distal EpoR cytoplasmic domain. Because this distal EpoR domain is essential for stress
erythropoiesis but dispensable for basal erythropoiesis, JAK2(V617F) may hijack EpoR-
dependent stress erythropoiesis pathways to drive erythrocytosis. Using a new flow
cytometry strategy, we identified a previously unrecognized population of early colony-
forming erythroid progenitors (CFU-E), which we named stress CFU-E or sCFU-E, as a
specific target of both the JAK2(V617F)-driven signals and the stress erythropoietic
response.
Elucidating EpoR signaling that supports sCFU-E expansion may reveal new therapeutic
avenues that can target erythrocytosis while sparing normal erythropoiesis. The central
goal of this proposal is to characterize the EpoR-dependent mechanisms that drive
sCFU-E expansion in stress erythropoiesis and in JAK2(V617F)-driven erythrocytosis.
Aim 1 determines mechanisms and EpoR signaling in sCFU-E expansion. Aim 2
leverages our new RNA-seq data to examine novel regulators downstream of EpoR in
stress erythropoiesis, murine erythrocytosis and human polycythemia vera. Together,
these results will elucidate mechanisms controlling stress erythropoiesis and
pathological erythrocytosis, and may lead to novel therapeutic interventions.

## Key facts

- **NIH application ID:** 9851893
- **Project number:** 5R01HL089966-12
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** LILY JUNSHEN HUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2007-09-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851893

## Citation

> US National Institutes of Health, RePORTER application 9851893, Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis (5R01HL089966-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851893. Licensed CC0.

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