Limited efficacy of BMS-911543 in a murine model of Janus kinase 2 V617F myeloproliferative neoplasm.
Activation of Janus kinase 2 (JAK2), frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and myelofibrosis, and it is thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2-selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34(+) progenitor cells from patients with JAK2(V617F)-positive MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction-transplantation model of JAK2(V617F) MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high-dose group and were maintained well below the levels in vehicle-treated mice throughout the study. However, BMS-911543 had no effect on red blood cell parameters. After 42 days of treatment, the proportion of JAK2(V617F)-positive cells in hematopoietic tissues was identical or slightly increased compared with controls. Plasma concentrations of interleukin 6, interleukin 15, and tumor necrosis factor α were elevated in MPN mice and reduced in the high-dose treatment group, whereas other cytokines were unchanged. Inhibitor activity after dosing was confirmed in a cell culture assay using the plasma of dosed mice and phosphorylated signal transducer and activator of transcription 5 flow cytometry. Collectively, these results show that BMS-911543 has limited activity in this murine model of JAK2(V617F)-driven MPN and suggest that targeting JAK2 alone may be insufficient to achieve effective disease control.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Anthony D
AD
Pomicter
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Anna M
AM
Eiring
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Anna V
AV
Senina
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Matthew S
MS
Zabriskie
Flow Cytometry Shared Resource, University of Utah, Salt Lake City, UT, USA.
James E
JE
Marvin
Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA.
Josef T
JT
Prchal
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA.
Thomas
T
O'Hare
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA. Electronic address: michael.deininger@hci.utah.edu.
Michael W
MW
Deininger
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011828:Radiation Chimera; D013154:Spleen / Q000473:pathology
D000970:Antineoplastic Agents; D016207:Cytokines; D006575:Heterocyclic Compounds, 3-Ring; C571029:N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C507924:JAK2 protein, human; D053614:Janus Kinase 2