Germline Lysine-Specific Demethylase 1 ( LSD1/KDM1A ) Mutations Confer Susceptibility to Multiple Myeloma

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...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2018-05, Vol.78 (10), p.2747-2759
Main Authors: Wei, Xiaomu, Calvo-Vidal, M Nieves, Chen, Siwei, Wu, Gang, Revuelta, Maria V, Sun, Jian, Zhang, Jinghui, Walsh, Michael F, Nichols, Kim E, Joseph, Vijai, Snyder, Carrie, Vachon, Celine M, McKay, James D, Wang, Shu-Ping, Jayabalan, David S, Jacobs, Lauren M, Becirovic, Dina, Waller, Rosalie G, Artomov, Mykyta, Viale, Agnes, Patel, Jayeshkumar, Phillip, Jude, Chen-Kiang, Selina, Curtin, Karen, Salama, Mohamed, Atanackovic, Djordje, Niesvizky, Ruben, Landgren, Ola, Slager, Susan L, Godley, Lucy A, Churpek, Jane, Garber, Judy E, Anderson, Kenneth C, Daly, Mark J, Roeder, Robert G, Dumontet, Charles, Lynch, Henry T, Mullighan, Charles G, Camp, Nicola J, Offit, Kenneth, Klein, Robert J, Yu, Haiyuan, Cerchietti, Leandro, Lipkin, Steven M
Format: Article
Language:English
Subjects:
Age
Animals
Benign monoclonal gammopathy
Cancer
Cell differentiation
Cell Line, Tumor
Cell self-renewal
Cyclin D2 - biosynthesis
Etiology
Gene expression
Genes, Tumor Suppressor
Genetic Predisposition to Disease - genetics
Genetics
Germ Cells - pathology
Hematopoietic stem cells
Histone Demethylases - antagonists & inhibitors
Histone Demethylases - genetics
Histone H3
Histones - metabolism
Humans
Immune response
Lymphocytes B
Lysine
Male
Mice
Mice, Inbred C57BL
Monoclonal Gammopathy of Undetermined Significance - genetics
Multiple myeloma
Multiple Myeloma - genetics
Mutation
Mutation, Missense - genetics
Myc protein
Paraproteins - analysis
Pathogenesis
Plasma
Plasma Cells - pathology
RNA Interference
RNA, Small Interfering - genetics
Stem cells
Transcription
Tumor suppressor genes
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Summary: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. KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. .
ISSN:0008-5472
1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-17-1900