Development of epigenetic therapy against multiple myeloma using a mouse model

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19497
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Iwama Atsushi 東京大学, 医科学研究所, 教授 (70244126)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 多発性骨髄腫 / エピジェネティクス / UTX / マウスモデル

Outline of Final Research Achievements

UTX/KDM6A, a histone H3K27 demethylase and a key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor suppressor function remains largely uncharacterized in multiple myeloma (MM). Here, we show that the conditional deletion of the X-linked Utx in germinal center (GC) derived cells collaborates with the activating BrafV600E mutation and promotes induction of lethal GC/post-GC B cell malignancies with MM-like plasma cell neoplasms being the most frequent. Utx loss in concert with BrafV600E only slightly induced MM-like profiles of transcriptome, chromatin accessibility, and H3K27 acetylation, however, it allowed plasma cells to gradually undergo full transformation through activation of transcriptional networks specific to MM that induce high levels of Myc expression. Our results reveal a tumor suppressor function of UTX in MM and implicate its insufficiency in the transcriptional reprogramming of plasma cells in the pathogenesis of MM.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究で作成に成功した多発性骨髄腫マウスモデルは、ヒトで認められる遺伝子変異を模倣したものであり、ヒト病態をよく反映するものである。様々な解析に応用可能であり、非常に有用な研究ツールとなる