title: Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors.
abstract: Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ifat
authors.initials: I
authors.lastname: Geron
authors.forename: Annelie E
authors.initials: AE
authors.lastname: Abrahamsson
authors.forename: Charlene F
authors.initials: CF
authors.lastname: Barroga
authors.forename: Edward
authors.initials: E
authors.lastname: Kavalerchik
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: John D
authors.initials: JD
authors.lastname: Hood
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Durocher
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Mak
authors.forename: Glenn
authors.initials: G
authors.lastname: Noronha
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Ken
authors.initials: K
authors.lastname: Kaushansky
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000235:genetics; D011087:Polycythemia Vera / Q000201:enzymology* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D033581:Stem Cell Transplantation; D014633:Valine / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D010649:Phenylalanine; D053614:Janus Kinase 2; D014633:Valine