Dissecting the tumor suppressive role of Utx in multiple myeloma

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16318
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Rizq Ola 東京大学, 医科学研究所, 特任研究員 (60823698)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: myeloma / UTX / Braf V600E / epigenetics / mature B cells / mouse model

Outline of Final Research Achievements

UTX, an X-linked histone demethylase, is inactivated/deleted in 1.5-4% of multiple myeloma (MM) patients. We established a novel myeloma mouse model in which Utx loss and Braf V600E mutation are combined. We observed a significantly shortened survival of compound mice compared to Cre negative control, single Utx loss or single Braf V600E KI. Add-back of WT or mutant UTX revealed that the cIDR domain is largely responsible for the tumor suppressor function of UTX while its demethylase activity is dispensable. Analysis of our RNA seq data from BM plasma cells from MM mice showed moderate transcriptomic reprogramming of plasma cells towards a myeloma-like transcriptome after a long latency. Our Utx/Braf mutant cells had largely different chromatin accessibility and H3K27ac status from control plasma cells. These data suggest that epigenomic reprogramming gradually proceeds in the absence of UTX and/or plasma cell clones that acquire myeloma-like properties are selected over time.

Free Research Field

Hematology

Academic Significance and Societal Importance of the Research Achievements

We developed a mouse model in which Utx loss and the activating Braf V600E mutation induced mature B-cell malignancies including multiple myeloma. We found that epigenomic reprogramming gradually proceeded and/or plasma cell clones that aquired myeloma-like properties were selected over time.