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

Cancer Res. 2018 May 15;78(10):2747-2759. doi: 10.1158/0008-5472.CAN-17-1900. Epub 2018 Mar 20.

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. Cancer Res; 78(10); 2747-59. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclin D2 / biosynthesis
  • Genes, Tumor Suppressor
  • Genetic Predisposition to Disease / genetics*
  • Germ Cells / pathology
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / genetics*
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monoclonal Gammopathy of Undetermined Significance / genetics*
  • Multiple Myeloma / genetics*
  • Mutation, Missense / genetics
  • Paraproteins / analysis
  • Plasma Cells / pathology
  • RNA Interference
  • RNA, Small Interfering / genetics

Substances

  • CCND2 protein, human
  • Cyclin D2
  • Histones
  • Paraproteins
  • RNA, Small Interfering
  • Histone Demethylases
  • KDM1A protein, human