Dissecting the tumor suppressive role of Utx in multiple myeloma

我们的研究表明，生发中心(GC)B细胞、GC后B细胞和浆细胞中UTX/Kdm6a的条件性缺失与激活的BRAFV600E突变协同作用，诱发包括多发性骨髓瘤(MM)样疾病在内的GC/GC后B细胞恶性肿瘤。发生MM样瘤的小鼠表现出骨髓和髓外器官中克隆性浆细胞的扩张，血清M蛋白和贫血。我们开发了一种小鼠细胞系，来源于一名患有骨髓瘤样疾病的垂死的UTX纯合子雌性患者的浆细胞性腹水。我们成功地将我们的新细胞系移植到亚致死剂量照射的免疫缺陷受体小鼠中。加入野生型UTX或去甲基酶失活突变体UTX可削弱UTX缺失的人MM细胞系RPMI8226的生长，而缺乏CIDR结构域的突变体UTX形成相分离的液体冷凝物，但未能抑制其生长。这表明CIDR结构域在很大程度上与UTX在MM中的催化活性无关的肿瘤抑制功能有关。UTX的丢失与BRAFV600E一起轻微诱导了MM样的转录组、染色质可及性和H3K27乙酰化。我们的结果揭示了UTX在MM中的肿瘤抑制功能，并表明它的丢失导致浆细胞转录重编程走向骨髓增生。

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.