title: The Jak2 inhibitor, G6, alleviates Jak2-V617F-mediated myeloproliferative neoplasia by providing significant therapeutic efficacy to the bone marrow.
abstract: We recently developed a Janus kinase 2 (Jak2) small-molecule inhibitor called G6 and found that it inhibits Jak2-V617F-mediated pathologic cell growth in vitro, ex vivo, and in vivo. However, its ability to inhibit Jak2-V617F-mediated myeloproliferative neoplasia, with particular emphasis in the bone marrow, has not previously been examined. Here, we investigated the efficacy of G6 in a transgenic mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. We found that G6 provided therapeutic benefit to the peripheral blood as determined by elimination of leukocytosis, thrombocytosis, and erythrocytosis. G6 normalized the pathologically high plasma concentrations of interleukin 6 (IL-6). In the liver, G6 eliminated Jak2-V617F-driven extramedullary hematopoiesis. With respect to the spleen, G6 significantly reduced both the splenomegaly and megakaryocytic hyperplasia. In the critically important bone marrow, G6 normalized the pathologically high levels of phospho-Jak2 and phospho-signal transducer and activator of transcription 5 (STAT5). It significantly reduced the megakaryocytic hyperplasia in the marrow and completely normalized the M/E ratio. Most importantly, G6 selectively reduced the mutant Jak2 burden by 67%on average, with virtual elimination of mutant Jak2 cells in one third of all treated mice. Lastly, clonogenic assays using marrow stem cells from the myeloproliferative neoplasm mice revealed a time-dependent elimination of the clonogenic growth potential of these cells by G6. Collectively, these data indicate that G6 exhibits exceptional efficacy in the peripheral blood, liver, spleen, and, most importantly, in the bone marrow, thereby raising the possibility that this compound may alter the natural history of Jak2-V617F-mediated myeloproliferative neoplasia.
authors: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Annet
authors: A
authors: Kirabo
authors: Sung O
authors: SO
authors: Park
authors: Anurima
authors: A
authors: Majumder
authors: Meghanath
authors: M
authors: Gali
authors: Mary K
authors: MK
authors: Reinhard
authors: Heather L
authors: HL
authors: Wamsley
authors: Zhizhuang Joe
authors: ZJ
authors: Zhao
authors: Christopher R
authors: CR
authors: Cogle
authors: Kirpal S
authors: KS
authors: Bisht
authors: György M
authors: GM
authors: Keserü
authors: Peter P
authors: PP
authors: Sayeski
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010649:Phenylalanine / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D014633:Valine / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D010649:Phenylalanine; D053614:Janus Kinase 2; D014633:Valine