The small molecule inhibitor G6 significantly reduces bone marrow fibrosis and the mutant burden in a mouse model of Jak2-mediated myelofibrosis

Am J Pathol. 2012 Sep;181(3):858-65. doi: 10.1016/j.ajpath.2012.05.033. Epub 2012 Jul 13.


Philadelphia chromosome-negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are disorders characterized by abnormal hematopoiesis. Among these myeloproliferative neoplasms, myelofibrosis has the most unfavorable prognosis. Furthermore, currently available therapies for myelofibrosis have little to no efficacy in the bone marrow and hence, are palliative. We recently developed a Janus kinase 2 (Jak2) small molecule inhibitor called G6 and found that it exhibits marked efficacy in a xenograft model of Jak2-V617F-mediated hyperplasia and a transgenic mouse model of Jak2-V617F-mediated polycythemia vera/essential thrombocytosis. However, its efficacy in Jak2-mediated myelofibrosis has not previously been examined. Here, we hypothesized that G6 would be efficacious in Jak2-V617F-mediated myelofibrosis. To test this, mice expressing the human Jak2-V617F cDNA under the control of the vav promoter were administered G6 or vehicle control solution, and efficacy was determined by measuring parameters within the peripheral blood, liver, spleen, and bone marrow. We found that G6 significantly reduced extramedullary hematopoiesis in the liver and splenomegaly. In the bone marrow, G6 significantly reduced pathogenic Jak/STAT signaling by 53%, megakaryocytic hyperplasia by 70%, and the Jak2 mutant burden by 68%. Furthermore, G6 significantly improved the myeloid to erythroid ratio and significantly reversed the myelofibrosis. Collectively, these results indicate that G6 is efficacious in Jak2-V617F-mediated myelofibrosis, and given its bone marrow efficacy, it may alter the natural history of this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Animals
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Disease Models, Animal
  • Hematopoiesis, Extramedullary / drug effects
  • Humans
  • Hyperplasia
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism*
  • Megakaryocytes / drug effects
  • Megakaryocytes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Myeloid Cells / drug effects
  • Myeloid Cells / pathology
  • Phosphorylation / drug effects
  • Primary Myelofibrosis / blood
  • Primary Myelofibrosis / drug therapy*
  • Primary Myelofibrosis / enzymology*
  • Primary Myelofibrosis / physiopathology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Reticulin / drug effects
  • Reticulin / metabolism
  • STAT5 Transcription Factor / metabolism
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Spleen / drug effects
  • Spleen / pathology
  • Spleen / physiopathology
  • Splenomegaly / complications
  • Splenomegaly / drug therapy
  • Splenomegaly / pathology
  • Splenomegaly / physiopathology
  • Stilbenes / pharmacology
  • Stilbenes / therapeutic use*


  • G6 stilbenoid tyrosine kinase inhibitor
  • Protein Kinase Inhibitors
  • Reticulin
  • STAT5 Transcription Factor
  • Small Molecule Libraries
  • Stilbenes
  • Janus Kinase 2