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.

Public Health Relevance

The poor understanding how red blood cells are produced poses a critical barrier to the development of artificial blood production systems, and of safer and more effective treatments for anemias and polycythemias, which affect millions of people in the U.S. This proposal aims to delineate molecular mechanisms that regulate erythropoiesis in erythropoietic stress and in polycythemia. Results from these studies will significantly improve our understanding of erythropoiesis and will shed light on the etiology of hematological malignancies and facilitate the design of novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089966-12
Application #
9851893
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Qasba, Pankaj
Project Start
2007-09-01
Project End
2022-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Lu, Zhigang; Xie, Jingjing; Wu, Guojin et al. (2017) Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med 23:79-90
Yao, H; Ma, Y; Hong, Z et al. (2017) Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm. Leukemia 31:2122-2131
Liu, Xiuli; Gogate, Aishwarya A; Tastemel, Melodi et al. (2017) Dynamic Change of Transcription Pausing through Modulating NELF Protein Stability Regulates Granulocytic Differentiation. Blood Adv 1:1358-1367
Leroy, Emilie; Dusa, Alexandra; Colau, Didier et al. (2016) Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 ?C helix. Biochem J 473:1579-91
Dutchak, Paul A; Laxman, Sunil; Estill, Sandi Jo et al. (2015) Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2. Cell Rep 12:371-9
Xu, Hui; He, Xiaojing; Zheng, Hui et al. (2014) Structural basis for the prion-like MAVS filaments in antiviral innate immunity. Elife 3:e01489
Kang, Chi-Chih; Huang, Wei-Chun; Kouh, Chiung-Wen et al. (2013) Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity. Integr Biol (Camb) 5:1217-28
Bulut, Gamze B; Sulahian, Rita; Yao, Huiyu et al. (2013) Cbl ubiquitination of p85 is essential for Epo-induced EpoR endocytosis. Blood 122:3964-72
Wan, Xiaobo; Ma, Yue; McClendon, Christopher L et al. (2013) Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure. PLoS Comput Biol 9:e1003022

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