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

Sep 24, 2026

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UTX/KDM6A is often lost or mutated in cancer, yet its tumor-suppressor role in multiple myeloma is not well defined. Conditional Utx deletion in germinal center–derived cells, together with activating BrafV600E, drives lethal GC/post-GC B-cell malignancies and MM-like plasma cell neoplasms. Affected mice show clonal plasma cell expansion, extramedullary disease, serum M proteins, and anemia. Rescue experiments indicate the cIDR domain mediates catalytic activity-independent tumor suppression, revealing Utx insufficiency in MM plasma-cell transcriptional reprogramming.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Epigenetic regulation of H3K27 methylation and PRC2

UTX/KDM6A functions and relevance to transcriptional reprogramming

Results overview

Conditional Utx deletion and synergy with BrafV600E

Phenotypes in mice and MM-like progression

Catalytic activity-independent tumor suppression via cIDR domain

Transcriptome and chromatin changes during transformation

Leukemia [www.nature.com/leu](www.nature.com/leu) ARTICLE OPEN MULTIPLE MYELOMA, GAMMOPATHIES UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease Ola Rizq 1,2,3,4,18, Naoya Mimura3,5,18 ✉, Motohiko Oshima 1,2, Shuji Momose 6, Naoya Takayama7, Naoki Itokawa 1, Shuhei Koide1, Asuka Shibamiya3, Yurie Miyamoto-Nagai3, Mohamed Rizk1,2, Yaeko Nakajima-Takagi1,2, Kazumasa Aoyama1,2, Changshan Wang2,8, Atsunori Saraya2, Ryoji Ito9, Masanori Seimiya 10, Mariko Watanabe 11, Satoshi Yamasaki12, Tatsuhiro Shibata 12, Kiyoshi Yamaguchi 13, Yoichi Furukawa13, Tetsuhiro Chiba14, Emiko Sakaida 3,5, Chiaki Nakaseko15, Jun-ichi Tamaru6, Yu-Tzu Tai 4, Kenneth C. Anderson 4, Hiroaki Honda 16 and Atsushi Iwama 1,2,17 ✉ © The Author(s) 2023, corrected publication 2023 | | 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 phaseseparated 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. | | | | | Leukemia (2023) 37:1895–1907; [https://doi.org/10.1038/s41375-023-01928-7](https://doi.org/10.1038/s41375-023-01928-7) | | | | | | INTRODUCTION Deregulation of histone modiﬁcations has been attributed to an imbalance between writers that install the histone methylation marks and erasers that remove these marks [1]. Speciﬁcally, alteration of the methylation of lysine 27 on histone H3 (H3K27) has an incriminating role in hematological malignancies [2, 3]. The catalytic components of polycomb repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2) and its homolog EZH1, deposit the repressive H3K27me3 mark at both promoters and enhancers [4]. The histone demethylase, ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (UTX), also known as KDM6A, speciﬁcally removes di- and tri-methyl groups from H3K27 thus antagonizing PRC2-mediated transcriptional repression [5]. UTX was identiﬁed as a critical regulator of reprogramming in induced pluripotent stem cells (iPSCs) through its catalytic activity by partnering with Oct4, Sox2, and KIF4 reprogramming factors [6]. In addition to its H3K27 demethylase activity, UTX possesses catalytic-independent functions. It contributes to embryonic viability, differentiation, and certain aspects of development in mouse embryonic stem cells (ESCs) independently of its demethylase activity [7–9]. Importantly, UTX isan integral component of the MLL3 and MLL4 COMPASS (complex of proteins associated with Set1) complexes, which monomethylate 1Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The In

FAQs

How does UTX/KDM6A relate to epigenetic control in multiple myeloma?

UTX/KDM6A removes di- and tri-methyl groups from H3K27, antagonizing PRC2-mediated transcriptional repression. The study investigates its tumor-suppressor function in multiple myeloma.

What happens when Utx is conditionally deleted in germinal center–derived cells?

Conditional deletion of X-linked Utx in germinal center-derived cells, especially with activating BrafV600E, promotes induction of lethal GC/post-GC B-cell malignancies and MM-like plasma cell neoplasms.

Which part of UTX is implicated in tumor suppression independent of catalytic activity?

Add-back experiments show that the cIDR domain, which forms phase-separated liquid condensates, is largely responsible for UTX’s catalytic activity-independent tumor suppressor function in MM cells.

Sep 24, 2026

Uploaded by Aditya