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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2747-2759 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma. / Wei, Xiaomu; Calvo-Vidal, M. Nieves; Chen, Siwei; Wu, Gang; Revuelta, Maria V.; Sun, Jian; Zhang, Jinghui; Walsh, Michael F.; Nichols, Kim E.; Joseph, Vijai; Snyder, Carrie; Vachon, Celine M; McKay, James D.; Wang, Shu Ping; Jayabalan, David S.; Jacobs, Lauren M.; Becirovic, Dina; Waller, Rosalie G.; Artomov, Mykyta; Viale, Agnes; Patel, Jayeshkumar; Phillip, Jude; Chen-Kiang, Selina; Curtin, Karen; Salama, Mohamed; Atanackovic, Djordje; Niesvizky, Ruben; Landgren, Ola; Slager, Susan L; Godley, Lucy A.; Churpek, Jane; Garber, Judy E.; Anderson, Kenneth C.; Daly, Mark J.; Roeder, Robert G.; Dumontet, Charles; Lynch, Henry T.; Mullighan, Charles G.; Camp, Nicola J.; Offit, Kenneth; Klein, Robert J.; Yu, Haiyuan; Cerchietti, Leandro; Lipkin, Steven M.
In: Cancer Research, Vol. 78, No. 10, 15.05.2018, p. 2747-2759.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma
AU - Wei, Xiaomu
AU - Calvo-Vidal, M. Nieves
AU - Chen, Siwei
AU - Wu, Gang
AU - Revuelta, Maria V.
AU - Sun, Jian
AU - Zhang, Jinghui
AU - Walsh, Michael F.
AU - Nichols, Kim E.
AU - Joseph, Vijai
AU - Snyder, Carrie
AU - Vachon, Celine M
AU - McKay, James D.
AU - Wang, Shu Ping
AU - Jayabalan, David S.
AU - Jacobs, Lauren M.
AU - Becirovic, Dina
AU - Waller, Rosalie G.
AU - Artomov, Mykyta
AU - Viale, Agnes
AU - Patel, Jayeshkumar
AU - Phillip, Jude
AU - Chen-Kiang, Selina
AU - Curtin, Karen
AU - Salama, Mohamed
AU - Atanackovic, Djordje
AU - Niesvizky, Ruben
AU - Landgren, Ola
AU - Slager, Susan L
AU - Godley, Lucy A.
AU - Churpek, Jane
AU - Garber, Judy E.
AU - Anderson, Kenneth C.
AU - Daly, Mark J.
AU - Roeder, Robert G.
AU - Dumontet, Charles
AU - Lynch, Henry T.
AU - Mullighan, Charles G.
AU - Camp, Nicola J.
AU - Offit, Kenneth
AU - Klein, Robert J.
AU - Yu, Haiyuan
AU - Cerchietti, Leandro
AU - Lipkin, Steven M.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047856035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047856035&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-1900
DO - 10.1158/0008-5472.CAN-17-1900
M3 - Article
C2 - 29559475
AN - SCOPUS:85047856035
VL - 78
SP - 2747
EP - 2759
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 10
ER -