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

UTX (also known as KDM6A) is a histone H3K27 demethylase that functions as a key component of the COMPASS complex implicated in enhancer activity through regulation of histone modifications and genome-wide re-organization. Loss or inactivating mutations of the X-linked UTX gene are found in multiple cancers; however, its tumor suppressor function remains largely uncharacterized in multiple myeloma (MM). Here, we show that the conditional deletion of Utx in germinal center (GC) B cells collaborates with the activating BrafV600E mutation and promotes induction of lethal GC/post-GC B cell neoplasms, such as B-cell lymphomas and plasma cell neoplasms, 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 demethylase activity-deficient UTX suppressed the proliferation of UTX-null MM cells, indicating that the catalytic activity is dispensable for its tumor suppressor function. Utx loss in concert with BrafV600E only slightly induced MM-like profiles of transcriptome and chromatin accessibility, 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.