Dissecting the tumor suppressive role of Utx in multiple myeloma

剖析 Utx 在多发性骨髓瘤中的肿瘤抑制作用

• 批准号: 22K16318
• 负责人: リズク モハメド・カーメル・アブデルバシール・ヘラル・オラ
• 金额: $ 2.91万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22K16318/
• 关键词: myeloma; mouse model; Epigenetics; UTX; BRAF V600E; KDM6A; Myeloma; tumor suppressor

Our study shows that the conditional deletion of Utx/Kdm6a in germinal center (GC) B cells, post-GC B cells and plasma cells collaborates with the activating BrafV600E mutation to induce GC/post-GC B cell malignancies including multiple myeloma (MM)-like disease in mice. Mice that developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow and extramedullary organs, serum M proteins, and anemia. We developed a murine cell line from plasmacytic ascites derived from a moribund compound Utx homozygous female that developed myeloma like disease. We successfully performed serial transplantation of our new cell line into sub-lethally irradiated immunodeficient recipient mice.Add-back of either wild-type UTX or a demethylase-inactive mutant UTX impaired the growth of UTX-null human MM cell line RPMI8226, while a mutant UTX lacking cIDR domain, that forms phase-separated liquid condensates, failed to suppress the growth. This suggests that cIDR domain is largely responsible for the catalytic activity-independent tumor suppressor function of UTX in MM.Utx loss together with BrafV600E slightly induced MM-like profiles of transcriptome, chromatin accessibility, and H3K27 acetylation.Our results uncover a tumor suppressor function of UTX in MM and suggest that its loss leads to transcriptional reprogramming of plasma cells towards myelomagenesis.

我们的研究表明，在小鼠中，在生发中心（GC）B细胞、GC后B细胞和浆细胞中Utx/Kdm 6a的条件性缺失与激活的BrafV 600 E突变协同诱导GC/GC后B细胞恶性肿瘤，包括多发性骨髓瘤（MM）样疾病。MM样肿瘤小鼠表现为骨髓和髓外器官中克隆性浆细胞的扩增、血清M蛋白和贫血。我们开发了一种小鼠细胞系，该细胞系来源于一名濒死的化合物Utx纯合雌性动物的浆细胞性腹水，该雌性动物发生了骨髓瘤样疾病。我们成功地将我们的新细胞系连续移植到亚致死剂量照射的免疫缺陷受体小鼠中，无论是野生型UTX还是去甲基酶失活的突变型UTX，都损害了UTX缺失的人MM细胞系RPMI 8226的生长，而缺乏cIDR结构域的突变型UTX，形成相分离的液体冷凝物，未能抑制生长。这表明，cIDR结构域是主要负责的催化活性无关的肿瘤抑制功能的UTX在MM。UTX的损失与BrafV 600 E轻微诱导MM样概况的转录组，染色质可及性，和H3 K27乙酰化。我们的研究结果揭示了肿瘤抑制功能的UTX在MM，并建议其损失导致转录重编程的浆细胞向骨髓瘤。

项目成果

Utx insufficiency cooperates with BrafV600E mutation in a mouse model of human multiple myeloma

Utx 不足与人类多发性骨髓瘤小鼠模型中的 BrafV600E 突变协同作用

• 发表时间: 2022
• 作者: Mitsuhashi Atsushi;Koyama Kazuya;Ogino Hirokazu;Afroj Tania;Nguyen Na Thi;Yoneda Hiroto;Otsuka Kenji;Sugimoto Masamichi;Kondoh Osamu;Nokihara Hiroshi;Hanibuchi Masaki;Takizawa Hiromitsu;Shinohara Tsutomu;Nishioka Yasuhiko;Ola Rizq
• 通讯作者: Ola Rizq