Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors.
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.
Geron
Ifat
I
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Abrahamsson
Annelie E
AE
Barroga
Charlene F
CF
Kavalerchik
Edward
E
Gotlib
Jason
J
Hood
John D
JD
Durocher
Jeffrey
J
Mak
Chi Ching
CC
Noronha
Glenn
G
Soll
Richard M
RM
Tefferi
Ayalew
A
Kaushansky
Ken
K
Jamieson
Catriona H M
CH
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
D047428:Protein Kinase Inhibitors; D010649:Phenylalanine; D053614:Janus Kinase 2; D014633:Valine