UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease

Author:

Rizq Ola,Mimura Naoya,Oshima Motohiko,Momose ShujiORCID,Takayama Naoya,Itokawa Naoki,Koide Shuhei,Shibamiya Asuka,Miyamoto-Nagai Yurie,Rizk Mohamed,Nakajima-Takagi Yaeko,Aoyama Kazumasa,Wang Changshan,Saraya Atsunori,Ito Ryoji,Seimiya Masanori,Watanabe Mariko,Yamasaki Satoshi,Shibata Tatsuhiro,Yamaguchi KiyoshiORCID,Furukawa Yoichi,Chiba Tetsuhiro,Sakaida EmikoORCID,Nakaseko Chiaki,Tamaru Jun-ichi,Tai Yu-TzuORCID,Anderson Kenneth C.ORCID,Honda Hiroaki,Iwama AtsushiORCID

Abstract

AbstractUTX/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.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Publisher

Springer Science and Business Media LLC

Subject

Oncology,Cancer Research,Hematology

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