1. Germline Lysine-Specific Demethylase 1 (
- Author
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Xiaomu, Wei, M Nieves, Calvo-Vidal, Siwei, Chen, Gang, Wu, Maria V, Revuelta, Jian, Sun, Jinghui, Zhang, Michael F, Walsh, Kim E, Nichols, Vijai, Joseph, Carrie, Snyder, Celine M, Vachon, James D, McKay, Shu-Ping, Wang, David S, Jayabalan, Lauren M, Jacobs, Dina, Becirovic, Rosalie G, Waller, Mykyta, Artomov, Agnes, Viale, Jayeshkumar, Patel, Jude, Phillip, Selina, Chen-Kiang, Karen, Curtin, Mohamed, Salama, Djordje, Atanackovic, Ruben, Niesvizky, Ola, Landgren, Susan L, Slager, Lucy A, Godley, Jane, Churpek, Judy E, Garber, Kenneth C, Anderson, Mark J, Daly, Robert G, Roeder, Charles, Dumontet, Henry T, Lynch, Charles G, Mullighan, Nicola J, Camp, Kenneth, Offit, Robert J, Klein, Haiyuan, Yu, Leandro, Cerchietti, and Steven M, Lipkin
- Subjects
Histone Demethylases ,Male ,Plasma Cells ,Mutation, Missense ,Monoclonal Gammopathy of Undetermined Significance ,Article ,Histones ,Mice, Inbred C57BL ,Mice ,Germ Cells ,Cell Line, Tumor ,Animals ,Cyclin D2 ,Humans ,Genes, Tumor Suppressor ,Genetic Predisposition to Disease ,RNA Interference ,RNA, Small Interfering ,Multiple Myeloma ,Paraproteins - Abstract
Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.
- Published
- 2017