JAK2 signaling in erythropoiesis

Summary

Principal Investigator: LILY JUNSHEN HUANG
Abstract: DESCRIPTION (provided by applicant): The Janus tyrosine kinase 2 (JAK2) plays an important role in hematopoiesis of multiple lineages, and a gain-of-function JAK2 mutation, V617F, is the major determinant in myeloproliferative neoplasms (MPNs). JAK2 kinase inhibitors showed hematological toxicity in treating MPNs, calling for novel therapeutics that can target only the affected lineage while sparing others. This task is hampered by lack of understanding in how JAK2 signaling regulates the generation of different blood cells. We propose to fill this knowledge gap by determining JAK2 signaling pathways that differentially drive erythropoiesis vs. granulopoiesis, and delineate two novel pathways utilized by JAK2 to regulate signaling and transcription for erythroid differentiation. The overall goal of this proposl is to characterize mechanisms underlying how JAK2 regulates erythropoiesis. Aim 1 will characterize a novel set of murine models;each expresses a different activating JAK2 mutant that results in a distinct MPN phenotype. We will determine whether different JAK2 mutants cause erythrocytosis or granulocytosis by promoting lineage-specific proliferation or by skewing differentiation in common progenitor compartments, and identify downstream signaling pathways required therein to cause different MPN phenotypes. We will also translate these mechanistic studies into the human setting. Aims 2 and 3 will dissect two novel molecular mechanisms for JAK2 to orchestrate signaling and transcription for erythroid differentiation, and examine their contribution in MPN development. Aim 2 will use both in vitro and in vivo experiments to characterize how JAK2 directs endocytosis of the erythropoietin receptor to terminate signaling. This process involves a new function of the p85 subunit of PI3K and is PI3K kinase activity-independent. Defects in this process result in prolonged signaling in primary and familial congenital polycythemia. In Aim 3, we will employ transcriptional profiling and genome-wide chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to delineate a novel pathway whereby JAK2 controls transcription, not by the canonical JAK-STAT pathway, but by regulating chromatin structure through phosphorylating the polycomb repression complex 2. Results from these studies will fill key gaps in our understanding of signaling in hematopoietic stem and progenitor cells that regulate both normal and excessive erythropoiesis. These results will also further our understanding of how Epo signaling is terminated, and will shift the paradigm of how JAK2 activates erythroid transcriptional network. In addition, these results will shed light on MPN biology and facilitate the design of novel and more effective therapeutic agents that specifically target affected lineage without compromising other lineages.
Funding Period: 2007-09-01 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia
    Rita Sulahian
    Departments of Cell Biology, University of Texas Southwestern Medical Center at Dallas, 75390 9039, USA
    Blood 113:5287-97. 2009
  2. pmc Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity
    Chi Chih Kang
    Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan
    Integr Biol (Camb) 5:1217-28. 2013
  3. pmc The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection
    Ming Chang Hu
    Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390 8885, USA
    Kidney Int 84:468-81. 2013
  4. pmc Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure
    Xiaobo Wan
    Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
    PLoS Comput Biol 9:e1003022. 2013
  5. pmc Erythroblastic sarcoma presenting as bilateral ovarian masses in an infant with pure erythroid leukemia
    Huan You Wang
    Department of Pathology, University of California San Diego Health Sciences, La Jolla, CA 92037 0987, USA
    Hum Pathol 42:749-58. 2011
  6. pmc Ubiquitination regulates the internalization, endolysosomal sorting, and signaling of the erythropoietin receptor
    Gamze Betul Bulut
    Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    J Biol Chem 286:6449-57. 2011
  7. pmc Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3zeta
    David M Patrick
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Genes Dev 24:1614-9. 2010
  8. pmc Advances in understanding the pathogenesis of primary familial and congenital polycythaemia
    Lily J Huang
    Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9039, USA
    Br J Haematol 148:844-52. 2010
  9. pmc Chemical and biological studies of nakiterpiosin and nakiterpiosinone
    Shuanhu Gao
    Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    J Am Chem Soc 132:371-83. 2010
  10. ncbi A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F)
    Lequn Zhao
    Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, U S A
    Biochem J 426:91-8. 2010

Research Grants

Detail Information

Publications12

  1. pmc Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia
    Rita Sulahian
    Departments of Cell Biology, University of Texas Southwestern Medical Center at Dallas, 75390 9039, USA
    Blood 113:5287-97. 2009
    ....
  2. pmc Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity
    Chi Chih Kang
    Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan
    Integr Biol (Camb) 5:1217-28. 2013
    ..Moreover, our results suggest that agents which can increase lysosomal membrane permeability may re-sensitize drug-resistant cancer cells to chemotherapeutic agents. ..
  3. pmc The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection
    Ming Chang Hu
    Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390 8885, USA
    Kidney Int 84:468-81. 2013
    ..Thus in the kidney, EpoR and its activity are downstream effectors of Klotho enabling it to function as a cytoprotective protein against oxidative injury. ..
  4. pmc Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure
    Xiaobo Wan
    Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
    PLoS Comput Biol 9:e1003022. 2013
    ....
  5. pmc Erythroblastic sarcoma presenting as bilateral ovarian masses in an infant with pure erythroid leukemia
    Huan You Wang
    Department of Pathology, University of California San Diego Health Sciences, La Jolla, CA 92037 0987, USA
    Hum Pathol 42:749-58. 2011
    ..Taken together, we showed, for the first time, that pure erythroid leukemia presented as a myeloid sarcoma in the form of ovarian masses...
  6. pmc Ubiquitination regulates the internalization, endolysosomal sorting, and signaling of the erythropoietin receptor
    Gamze Betul Bulut
    Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    J Biol Chem 286:6449-57. 2011
    ..We therefore propose that ubiquitination of the EpoR critically controls both receptor down-regulation and downstream signaling...
  7. pmc Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3zeta
    David M Patrick
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Genes Dev 24:1614-9. 2010
    ..These findings reveal an essential role of 14-3-3zeta as a mediator of the proerythroid differentiation actions of miR-451, and highlight the therapeutic potential of miR-451 inhibitors...
  8. pmc Advances in understanding the pathogenesis of primary familial and congenital polycythaemia
    Lily J Huang
    Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9039, USA
    Br J Haematol 148:844-52. 2010
    ..Truncated PFCP EpoRs are not properly down-regulated upon stimulation, underscoring the importance of these mechanisms in the pathogenesis of PFCP...
  9. pmc Chemical and biological studies of nakiterpiosin and nakiterpiosinone
    Shuanhu Gao
    Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    J Am Chem Soc 132:371-83. 2010
    ..Nakiterpiosin may be useful as an anticancer agent in those tumors resistant to existing antimitotic agents and those dependent on Hedgehog pathway responses for growth...
  10. ncbi A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F)
    Lequn Zhao
    Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, U S A
    Biochem J 426:91-8. 2010
    ..The results of the present study provide the biochemical basis for how V617F hyperactivates JAK2, and identifies novel regulating roles of the JAK2 FERM domain to control kinase activity at different activation states...
  11. pmc A JAK2 interdomain linker relays Epo receptor engagement signals to kinase activation
    Lequn Zhao
    Department of Cell Biology, University of Texas SouthwesternMedical Center, Dallas, Texas 75390, USA
    J Biol Chem 284:26988-98. 2009
    ..These results suggest that the SH2-pseudokinase domain linker acts as a switch that relays cytokine engagement to JAK2 activation by flexing the pseudokinase domain hinge...
  12. pmc Cbl ubiquitination of p85 is essential for Epo-induced EpoR endocytosis
    Gamze B Bulut
    Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
    Blood 122:3964-72. 2013
    ..Our results uncover a novel Cbl/p85/epsin-1 pathway in EpoR endocytosis and show that defects in this pathway contribute to excessive Epo signaling and erythroid hyperproliferation in PFCP. ..

Research Grants30

  1. Erythropoietin in Non-Erythroid Cells: Function and Regulation
    Josef T Prchal; Fiscal Year: 2013
    ..The possibility that Epo may play a beneficial as well as detrimental role in endothelial/cardiovascular, neurological abnormalities, and cancers is relevant to a significant portion of VA patients. ..
  2. Control of the Erythroid Terminal Differentiation Decision
    Arthur I Skoultchi; Fiscal Year: 2013
    ..The successful completion of this work will enable the development of new approaches to managing defects in red blood cell production that occur in chronic and acute anemia due to a variety of causes. ..
  3. Epigenetic Control of Hematopoietic Gene Expression
    Gerd A Blobel; Fiscal Year: 2013
    ..Moreover, we study mechanisms by which cells "remember" their identity throughout the cell cycle. Progress is this area promises novel approaches to treat blood-related disorders including leukemias and anemias. ..
  4. Hematopoietic Regulation Via GATA Switches
    Emery H Bresnick; Fiscal Year: 2013
    ..As GATA switches involving other GATA factors are likely to occur in a wide spectrum of cells, the results are expected to have broad biological and pathophysiological importance. ..
  5. Mechanisms of Impaired Erythropoiesis in Post Burn Anemia of Critical Illness
    KUZHALI MUTHUMALAIAPPAN; Fiscal Year: 2013
    ..Results gleaned from the experimental model combined with clinical data will provide the mechanistic insight into post burn anemia, which will pave the way for potential therapeutic interventions to treat anemia of critical illness. ..
  6. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  7. Arterial Dysfunction: Basic and Clinical Mechanisms
    Thomas Michel; Fiscal Year: 2013
    ..Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman. ..
  8. Molecular Pathways to Thynmic Lymphoma and Leukemia
    A Thomas Look; Fiscal Year: 2013
    ..Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. ..
  9. The Role of the Histone Methyltransferase DOT1L in Erythropoiesis
    Patrick E Fields; Fiscal Year: 2013
    ..We will determine the effects of DOT1L loss on HSC function and differentiation using colony assays from fetal liver- and bone marrow-derived HSC. ..
  10. Role of TET proteins in myeloid malignancies
    Anjana Rao; Fiscal Year: 2013
    ..This information will help us understand how changes that occur as a result of somatic mutations in these gene products in stem cells might predispose to myeloid cancers in humans. ..
  11. HSC Diversity: Regulation by Clonal Selection vs Epigenetic Induction
    Irving L Weissman; Fiscal Year: 2013
    ....
  12. Transcriptional Networks Controlling Erythroid Differentiation
    Gerd A Blobel; Fiscal Year: 2013
    ..Together, the proposed studies are designed to elucidate the transcriptional and epigenetic machinery that underlies the establishment and stable propagation of gene expression patterns in the hematopoietic system. ..
  13. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
    ..This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract) ..
  14. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
    ..abstract_text> ..