Regulation of the pathogenesis of myeloproliferative neoplasms with a focus on IFNalpha signaling and the mechanism of renal dysfunction.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17404
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Tahira Yuki 宮崎大学, 医学部, 医員 (10868243)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: MPN / IFNα / TYK2 / MPN関連腎症

Outline of Final Research Achievements

IFNα has been used as a cytoreductive therapy for myeloproliferative neoplasms, but the detailed signaling mechanisms are unknown. To elucidate the roles of JAK1 and TYK2 downstream of the signaling, we used knockout mice and investigated the role of each molecule. In TYK2-KO mice, the therapeutic effect and signal attenuation of IFNα were observed, indicating that TYK2 is an essential molecule.
We also confirmed that Jak2V617F transgenic mice can exhibit renal dysfunction similar to those reported in humans with MPN-associated nephropathy. We plan to further analyze this mouse model to elucidate the mechanism of renal dysfunction.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

MPNの中でもprimary myelofibrosis (PMF)の生存期間中央値は4年と短く、極めて予後不良である。同種造血幹細胞移植を除き、JAK阻害薬など現行の治療法では治癒を望めない。腎病変を合併した場合、移植さえ行うことができないのが現状であり、臨床的なunmet needsがある。本研究により、腎病変のメカニズムが明らかになり、かつ腫瘍幹細胞を標的とした新規IFNα/JAK阻害薬併用療法の開発ができれば、多くの症例で予後の改善につながることが期待される。