title: JAK2 V617F stimulates proliferation of erythropoietin-dependent erythroid progenitors and delays their differentiation by activating Stat1 and other nonerythroid signaling pathways.
abstract: JAK2 V617F is a mutant-activated JAK2 kinase found in most polycythemia vera (PV) patients; it skews normal proliferation and differentiation of hematopoietic stem and progenitor cells and simulates aberrant expansion of erythroid progenitors. JAK2 V617F is known to activate some signaling pathways not normally activated in mature erythroblasts, but there has been no systematic study of signal transduction pathways or gene expression in erythroid cells expressing JAK2 V617F undergoing erythropoietin (Epo)-dependent terminal differentiation. Here we report that expression of JAK2 V617F in murine fetal liver Epo-dependent progenitors allows them to divide approximately six rather than the normal approximately four times in the presence of Epo, delaying their exit from the cell cycle. Over time, the number of red cells formed from each Epo-dependent progenitor increases fourfold, and these cells eventually differentiate into normal enucleated reticulocytes. We report that purified fetal liver Epo-dependent progenitors express many cytokine receptors additional to the EpoR. Expression of JAK2 V617F triggers activation of Stat5, the only STAT normally activated by Epo, as well as activation of Stat1 and Stat3. Expression of JAK2 V617F also leads to transient induction of many genes not normally activated in terminally differentiating erythroid cells and that are characteristic of other hematopoietic lineages. Inhibition of Stat1 activation blocks JAK2 V617F hyperproliferation of erythroid progenitors, and we conclude that Stat1-mediated activation of nonerythroid signaling pathways delays terminal erythroid differentiation and permits extended cell divisions.
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA; Departments of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong.
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Hu
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA; Departments of Biology and Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA. Electronic address: lodish@wi.mit.edu.
authors.forename: Harvey
authors.initials: H
authors.lastname: Lodish
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003062:Codon; D003114:Colony-Forming Units Assay; D000066630:Ectopic Gene Expression; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D003062:Codon; D017467:Receptors, Erythropoietin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D004921:Erythropoietin; C507924:JAK2 protein, human; D053614:Janus Kinase 2