An inhibitor of Janus kinase 2 prevents polycythemia in mice.
Polycythemia vera (PV) is a myeloproliferative disorder characterized by increased red cell mass and splenomegaly in the absence of secondary causes [Tefferi A., Spivak J.L., Polycythemia vera: scientific advances and current practice. Semin Hematol 2005;42(4):206-20.]. Recently, several laboratories have discovered that the vast majority of patients with PV carry a single, activating mutation (V617F) in the pseudokinase domain of Janus kinase 2 (Jak2) [Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, et al., Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280(24):22788-92; James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al., A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature 2005;434(7037):1144-8; Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al., A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352(17):1779-90; Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4):387-97.]. This discovery has spurred interest in developing therapies for PV via inhibition of Jak2. We induced polycythemia in mice by administering high dose recombinant erythropoietin (Epo) and determined that administration recapitulates almost all of the major and minor diagnostic features of human PV. We then tested a selective, small molecule inhibitor of Jak2 (Jak2i) and showed that this treatment prevents polycythemia. This prevention of polycythemia was accompanied by lower hematocrits, reduced spleen sizes and reductions in Stat5 phosphorylation (pStat5). Surprisingly, Epo rapidly (<1h) induces mobilization of activated erythroid precursors into the blood, thus allowing drug-response relationships to guide discovery. We conclude that inhibition of Jak2 prevents polycythemia in mice, and furthermore present this model as an efficient tool for the discovery of drugs that effectively treat human PV.
Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Anjili
A
Mathur
Jan-Rung
JR
Mo
Manfred
M
Kraus
Erin
E
O'Hare
Peter
P
Sinclair
Jonathan
J
Young
Shuxia
S
Zhao
Yuxun
Y
Wang
Johnny
J
Kopinja
Xianlu
X
Qu
John
J
Reilly
Deborah
D
Walker
Lin
L
Xu
Daniel
D
Aleksandrowicz
Gary
G
Marshall
Martin L
ML
Scott
Nancy E
NE
Kohl
Eric
E
Bachman
D000818:Animals; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015672:Erythroid Precursor Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011086:Polycythemia / Q000517:prevention & control*; D011087:Polycythemia Vera / Q000503:physiopathology*; D055728:Primary Myelofibrosis / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D015398:Signal Transduction; D013920:Thrombocythemia, Essential; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011728:Pyridones; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2