Development of epigenetic therapy against multiple myeloma using a mouse model

• 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
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 多発性骨髄腫 / エピジェネティクス / UTX / マウスモデル / エピジェネティック治療標的

Outline of Research at the Start

多発性骨髄腫の悪性度や治療抵抗性に関与すると想定されるH3K27脱メチル化酵素UTXの機能喪失型変異を模倣したマウスの作成に成功した。すなわち、Utxを胚中心B細胞特異的に欠損し、Ras経路の活性型変異を同時に発現するマウスを作成したところ、多発性骨髄腫様の腫瘍を発症することを見出した。本研究においてはこの新規多発性骨髄腫モデルを用いたエピジェネティック関連遺伝子のCRISPR/Cas9スクリーニングを行い、多発性骨髄腫治療のエピジェネティック標的分子をプロファイリングし、新規エピジェネティック治療法の開発を行う。

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.

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

Research Products

• [Int'l Joint Research] スローンケタリングがんセンター(米国)
• [Int'l Joint Research] PTC Therapeutics(米国)
• [Journal Article] UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease (2023)
  • Author(s): Rizq O, Mimura N, Oshima M, Momose S, Takayama N, Koide S, Shibamiya A, Nagai Y, Rizk M, Itokawa N, Nakajima-Takagi Y, Aoyama K, Wang C, Saraya A, Seimiya M, Watanabe M, Yamasaki S, Shibat T, Yamaguchi K, Furukawa Y, Sakaida E, Nakaseko C, Tamaru J, Tai Y-T, Anderson KC, Honda H, and Iwama A.
  • Journal Title: Leukemia Volume: －
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The pathogenetic significance of exhausted T cells in a mouse model of mature B cell neoplasms (2023)
  • Author(s): 1.Shibamiya A, Miyamoto-Nagai Y, Koide S, Oshima M, Rizq O, Aoyama K, Nakajima-Takagi Y, Kato R, Kayamori K, Isshiki Y, Oshima-Hasegawa N, Muto T, Tsukamoto S, Takeda Y, Koyama-Nasu R, Chiba T, Honda H, Yokote K, Iwama A, Sakaida E, Mimura N.
  • Journal Title: Cancer Immunol Immunother Volume: － Issue: 8 Pages: 2635-2648
  • DOI: 10.1007/s00262-023-03447-x
  • Peer Reviewed / Open Access
• [Journal Article] The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells. (2021)
  • Author(s): Nagai Y, Mimura N, Nakaseko C et al
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 2074-2074
  • DOI: 10.1038/s41598-021-81577-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease (2022)
  • Author(s): 13.Ola Rizq, Naoya Mimura, Shuhei Koide, Motohiko Oshima, Shuji Momose, Yaeko Nakajima-Takagi, Kazumasa, Aoyama, Emiko Sakaida, Chiaki Nakaseko, Junichi Tamaru, Hiroaki Honda, Atsushi Iwama
  • Organizer: The 81th Annual Meeting of the Japanese Cancer Association
• [Remarks] 幹細胞分子医学
  • URL: https://www.ims.u-tokyo.ac.jp/molmed/