UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease.
UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease.
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DOI：
10.1038/s41375-023-01928-7
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发表时间：
2023-09
期刊：
影响因子：
11.4
通讯作者：
Iwama, Atsushi
中科院分区：
文献类型：
--
作者：
Rizq, Ola;Mimura, Naoya;Oshima, Motohiko;Momose, Shuji;Takayama, Naoya;Itokawa, Naoki;Koide, Shuhei;Shibamiya, Asuka;Miyamoto-Nagai, Yurie;Rizk, Mohamed;Nakajima-Takagi, Yaeko;Aoyama, Kazumasa;Wang, Changshan;Saraya, Atsunori;Seimiya, Masanori;Watanabe, Mariko;Yamasaki, Satoshi;Shibata, Tatsuhiro;Yamaguchi, Kiyoshi;Furukawa, Yoichi;Chiba, Tetsuhiro;Sakaida, Emiko;Nakaseko, Chiaki;Tamaru, Jun-ichi;Tai, Yu-Tzu;Anderson, Kenneth C.;Honda, Hiroaki;Iwama, Atsushi
UTX/KDM 6A是一种组蛋白H3 K27去甲基化酶，也是COMPASS复合物的关键组分，在癌症中经常丢失或突变;然而，其肿瘤抑制功能在多发性骨髓瘤（MM）中仍然很大程度上未被表征。在这里，我们表明，条件性删除的X-连锁UTX在生发中心（GC）衍生的细胞与激活BrafV 600 E突变，促进诱导致死性GC/后GC B细胞恶性肿瘤MM样浆细胞肿瘤是最常见的。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。野生型UTX或一系列突变体的加回显示，形成相分离的液体冷凝物的cIDR结构域在很大程度上负责UTX在MM细胞中的催化活性独立的肿瘤抑制功能。与BrafV 600 E一致的Utx丢失仅轻微诱导转录组、染色质可及性和H3 K27乙酰化的MM样谱，然而，其允许浆细胞通过激活MM特异性的转录网络逐渐经历完全转化，所述转录网络诱导高水平的Myc表达。我们的研究结果揭示了UTX在MM中的肿瘤抑制功能，并暗示其在MM发病机制中浆细胞转录重编程的不足。
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. Mice that developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow and extramedullary organs, serum M proteins, and anemia. Add-back of either wild-type UTX or a series of mutants revealed that cIDR domain, that forms phase-separated liquid condensates, is largely responsible for the catalytic activity-independent tumor suppressor function of UTX in MM cells. 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.
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影响因子：
4.6
作者：
Baker EK;Taylor S;Gupte A;Sharp PP;Walia M;Walsh NC;Zannettino AC;Chalk AM;Burns CJ;Walkley CR
通讯作者：
Walkley CR
影响因子：
8.8
作者：
Ezponda T;Dupéré-Richer D;Will CM;Small EC;Varghese N;Patel T;Nabet B;Popovic R;Oyer J;Bulic M;Zheng Y;Huang X;Shah MY;Maji S;Riva A;Occhionorelli M;Tonon G;Kelleher N;Keats J;Licht JD
通讯作者：
Licht JD
影响因子：
11.4
作者：
Brass, AL;Zhu, AQ;Singh, H
通讯作者：
Singh, H
DOI：
10.1073/pnas.0707292104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Hong, SunHwa;Cho, Young-Wook;Ge, Kai
通讯作者：
Ge, Kai
影响因子：
82.9
作者：
Ortega-Molina A;Boss IW;Canela A;Pan H;Jiang Y;Zhao C;Jiang M;Hu D;Agirre X;Niesvizky I;Lee JE;Chen HT;Ennishi D;Scott DW;Mottok A;Hother C;Liu S;Cao XJ;Tam W;Shaknovich R;Garcia BA;Gascoyne RD;Ge K;Shilatifard A;Elemento O;Nussenzweig A;Melnick AM;Wendel HG
通讯作者：
Wendel HG