Molecular mechanism of treatment-resistant symptoms in myelofibrosis

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860738
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: Shide Kotaro 宮崎大学, 医学部, 助教 (20468028)
• Co-Investigator(Renkei-kenkyūsha): KAMEDA Takuro 宮崎大学, 医学部, 医員 (30468029)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 骨髄線維症

Outline of Final Research Achievements

For the treatment of primary myelofibrosis and post-PV, post-ET myelofibrosis, the small molecule inhibitors of JAK2 have shown a remarkable therapeutic effect. The drugs are very effective in splenomegaly and constitutional symptoms, on the other hand have no effect on bone marrow fibrosis and anemia. In this study, we studied the molecular mechanisms of these refractory symptoms using JAK2 V617F transgenic mice. (1) Bone marrow fibrosis: We identified that JAK2 mutation activates MEK-ERK1/2 pathway downstream of MPL and may contribute to TGFβ1 overproduction, causing bone marrow fibrosis via transcriptional enhancement of USF1, and MEK inhibition improve bone marrow fibrosis. (2)Anemia and drug resistance: We showed that TYK2 defects does not affect the anemia or inhibitor resistance of the transgenic mice. (3)The role of epigenetic abnormality: We identified that loss of TET2 accelerates the degree of malignancy and sustains MPNs in combination with JAK2V617F.

Free Research Field

血液内科学