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Germline Lysine-Specific Demethylase 1 () Mutations Confer Susceptibility to Multiple Myeloma.

TitleGermline Lysine-Specific Demethylase 1 () Mutations Confer Susceptibility to Multiple Myeloma.
Publication TypeJournal Article
Year of Publication2018
AuthorsWei X, M Calvo-Vidal N, Chen S, Wu G, Revuelta MV, Sun J, Zhang J, Walsh MF, Nichols KE, Joseph V, Snyder C, Vachon CM, McKay JD, Wang S-P, Jayabalan DS, Jacobs LM, Becirovic D, Waller RG, Artomov M, Viale A, Patel J, Phillip J, Chen-Kiang S, Curtin K, Salama M, Atanackovic D, Niesvizky R, Landgren O, Slager SL, Godley LA, Churpek J, Garber JE, Anderson KC, Daly MJ, Roeder RG, Dumontet C, Lynch HT, Mullighan CG, Camp NJ, Offit K, Klein RJ, Yu H, Cerchietti L, Lipkin SM
JournalCancer Res
Volume78
Issue10
Pagination2747-2759
Date Published2018 May 15
ISSN1538-7445
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. 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. .

DOI10.1158/0008-5472.CAN-17-1900
Alternate JournalCancer Res.
PubMed ID29559475
PubMed Central IDPMC5955848
Grant ListR01 CA178765 / CA / NCI NIH HHS / United States
R21 CA152336 / CA / NCI NIH HHS / United States
T15 LM007124 / LM / NLM NIH HHS / United States
S10 OD018522 / OD / NIH HHS / United States
R01 CA167824 / CA / NCI NIH HHS / United States
R01 CA134674 / CA / NCI NIH HHS / United States
HHSN261201000026C / CA / NCI NIH HHS / United States
P30 CA042014 / CA / NCI NIH HHS / United States