@article{96cdaf2c527e4039ab521a341c7b6dc9,
title = "Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma",
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. Significance: 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.",
author = "Xiaomu Wei and Calvo-Vidal, {M. Nieves} and Siwei Chen and Gang Wu and Revuelta, {Maria V.} and Jian Sun and Jinghui Zhang and Walsh, {Michael F.} and Nichols, {Kim E.} and Vijai Joseph and Carrie Snyder and Vachon, {Celine M.} and McKay, {James D.} and Wang, {Shu Ping} and Jayabalan, {David S.} and Jacobs, {Lauren M.} and Dina Becirovic and Waller, {Rosalie G.} and Mykyta Artomov and Agnes Viale and Jayeshkumar Patel and Jude Phillip and Selina Chen-Kiang and Karen Curtin and Mohamed Salama and Djordje Atanackovic and Ruben Niesvizky and Ola Landgren and Slager, {Susan L.} and Godley, {Lucy A.} and Jane Churpek and Garber, {Judy E.} and Anderson, {Kenneth C.} and Daly, {Mark J.} and Roeder, {Robert G.} and Charles Dumontet and Lynch, {Henry T.} and Mullighan, {Charles G.} and Camp, {Nicola J.} and Kenneth Offit and Klein, {Robert J.} and Haiyuan Yu and Leandro Cerchietti and Lipkin, {Steven M.}",
note = "Funding Information: K.E. Nichols reports receiving commercial research grants from Incyte and Alpine Biosciences. L.A. Godley has provided expert testimony for UpToDate, Inc. J.E. Garber reports receiving commercial research support from Novartis Pharmaceuticals, is a consultant/advisory board member for Novartis Pharmaceuticals, GTC Pharmaceuticals, and Helix Genetics, and has provided expert testimony for Oric Pharmacetuicals. C.G. Mullighan reports receiving commercial research grants from Loxo Oncology, Pfizer, and Abbvie, has received speakers bureau honoraria from Amgen, and is a consultant/advisory board Funding Information: We acknowledge funding from R01 CA167824, R01 CA13464, R01 CA178765, T15 LM007124, R21 CA152336, LLS 6067-09, NCI P30 CA42014, HHSN261201000026C, the V Foundation (V2015-003), the Weill-Cornell Program in Mendelian Genetics, the Utah Genome Project, Huntsman Cancer Institute, Utah Population Database (UPDB), the Utah Cancer Registry (UCR), Icahn School of Medicine at Mount Sinai Office of Research Infrastructure of the NIH award number S10OD018522, and a generous donation from Matthew Bell. Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = may,
day = "15",
doi = "10.1158/0008-5472.CAN-17-1900",
language = "English (US)",
volume = "78",
pages = "2747--2759",
journal = "Cancer Research",
issn = "0008-5472",
number = "10",
}