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. 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. .

Global Burden of Multiple Myeloma

“… 22 In addition, there have been recently described autosomal germline mutations that can predispose a patient to MM. 23 At least some of the differences in incidence may be due to lack of diagnostic abilities in lower SDI countries compared with high SDI countries and do not necessarily reflect differences in disease biology (eFigure 6 in the Supplement shows a map of the SDI quintiles). Supporting this hypothesis is the fact that the disease burden of MM in African Americans in the United States is markedly higher than that of European Americans in the United States, yet the disease burden among Africans living in Africa is among the lowest in the world, as shown in our study and in previous studies.…”

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

“…Particularly, cytogenetic changes such as hyperdiploidy or translocations involving recurrent oncogenes and the immunoglobulin heavy chain locus are considered initiating events (4). In some individuals, inherited alleles (i.e., germline polymorphisms) can increase the risk of developing MM but this is considered a rare occurrence and all alleles identified so far have been shown to only confer a small risk (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). On the contrary, gene mutations are frequent in newly diagnosed MM (NDMM) and have been particularly characterized since the advent of next generation sequencing (NGS) technologies (15)(16)(17)(18)(19)(20)(21)(22).…”

Treatment evolution and improved survival in multiple myeloma in Taiwan

“…Exposure to farm work, printing and cleaning occupations appear to have some association with an increased risk of MM [19,20]. Some studies have identified numerous predisposing genetic factors for MM [21][22][23]. However, as yet, the role of these exposures and the distribution of genetic susceptibility among different population groups have not been evaluated.…”