Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis.
The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Priya
P
Koppikar
Omar
O
Abdel-Wahab
Cyrus
C
Hedvat
Sachie
S
Marubayashi
Jay
J
Patel
Aviva
A
Goel
Nicole
N
Kucine
Jeffrey R
JR
Gardner
Andrew P
AP
Combs
Kris
K
Vaddi
Patrick J
PJ
Haley
Timothy C
TC
Burn
Mark
M
Rupar
Jacqueline F
JF
Bromberg
Mark L
ML
Heaney
Elisa
E
de Stanchina
Jordan S
JS
Fridman
Ross L
RL
Levine
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010976:Platelet Count; D055728:Primary Myelofibrosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013922:Thrombocytosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics
C481270:Mpl protein, mouse; D047428:Protein Kinase Inhibitors; D053628:Receptors, Thrombopoietin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2