Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma Journal Article


Authors: Wei, X.; Calvo-Vidal, M. N.; Chen, S.; Wu, G.; Revuelta, M. V.; Sun, J.; Zhang, J.; Walsh, M. F.; Nichols, K. E.; Joseph, V.; Snyder, C.; Vachon, C. M.; McKay, J. D.; Wang, S. P.; Jayabalan, D. S.; Jacobs, L. M.; Becirovic, D.; Waller, R. G.; Artomov, M.; Viale, A.; Patel, J.; Phillip, J.; Chen-Kiang, S.; Curtin, K.; Salama, M.; Atanackovic, D.; Niesvizky, R.; Landgren, O.; Slager, S. L.; Godley, L. A.; Churpek, J.; Garber, J. E.; Anderson, K. C.; Daly, M. J.; Roeder, R. G.; Dumontet, C.; Lynch, H. T.; Mullighan, C. G.; Camp, N. J.; Offit, K.; Klein, R. J.; Yu, H.; Cerchietti, L.; Lipkin, S. M.
Article 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. © 2018 American Association for Cancer Research.
Keywords: controlled study; human cell; major clinical study; missense mutation; nonhuman; mouse; animal tissue; familial disease; multiple myeloma; animal experiment; genetic transcription; plasma cell; immune response; genetic susceptibility; myc protein; upregulation; monoclonal immunoglobulinemia; cell expansion; germline mutation; paraprotein; human; priority journal; article; kdm1a gene; lsd1 gene
Journal Title: Cancer Research
Volume: 78
Issue: 10
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2018-05-15
Start Page: 2747
End Page: 2759
Language: English
DOI: 10.1158/0008-5472.can-17-1900
PROVIDER: scopus
PMCID: PMC5955848
PUBMED: 29559475
DOI/URL:
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Kenneth Offit
    791 Offit
  2. Agnes Viale
    246 Viale
  3. Vijai Joseph
    213 Joseph
  4. Lauren Michelle Jacobs
    17 Jacobs
  5. Carl Ola Landgren
    336 Landgren
  6. Michael Francis Walsh
    156 Walsh