Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma

Xiaomu Wei, M. Nieves Calvo-Vidal, Siwei Chen, Gang Wu, Maria V. Revuelta, Jian Sun, Jinghui Zhang, Michael F. Walsh, Kim E. Nichols, Vijai Joseph, Carrie Snyder, Celine M. Vachon, James D. McKay, Shu Ping Wang, David S. Jayabalan, Lauren M. Jacobs, Dina Becirovic, Rosalie G. Waller, Mykyta Artomov, Agnes Viale & 24 others Jayeshkumar Patel, Jude Phillip, Selina Chen-Kiang, Karen Curtin, Mohamed Salama, Djordje Atanackovic, Ruben Niesvizky, Ola Landgren, Susan L. Slager, Lucy A. Godley, Jane Churpek, Judy E. Garber, Kenneth C. Anderson, Mark J. Daly, Robert G. Roeder, Charles Dumontet, Henry T. Lynch, Charles G. Mullighan, Nicola J. Camp, Kenneth Offit, Robert J. Klein, Haiyuan Yu, Leandro Cerchietti, Steven M. Lipkin

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2747-2759
Number of pages13
JournalCancer Research
Volume78
Issue number10
DOIs
StatePublished - May 15 2018

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Multiple Myeloma
Lysine
Mutation
Monoclonal Gammopathy of Undetermined Significance
Germinal Center
Plasma Cells
Cell Differentiation
B-Lymphocytes
Paraproteins
Dominant Genes
Germ-Line Mutation
Gene Expression Profiling
Missense Mutation
Hematopoietic Stem Cells
Epigenomics
Histones
Genes
Neoplasms
Up-Regulation
Antigens

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wei, X., Calvo-Vidal, M. N., Chen, S., Wu, G., Revuelta, M. V., Sun, J., ... Lipkin, S. M. (2018). Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma. Cancer Research, 78(10), 2747-2759. https://doi.org/10.1158/0008-5472.CAN-17-1900

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 journalArticle

Wei, X, Calvo-Vidal, MN, Chen, S, Wu, G, Revuelta, MV, Sun, J, Zhang, J, Walsh, MF, Nichols, KE, Joseph, V, Snyder, C, Vachon, CM, McKay, JD, Wang, SP, Jayabalan, DS, Jacobs, LM, Becirovic, D, Waller, RG, Artomov, M, Viale, A, Patel, J, Phillip, J, Chen-Kiang, S, Curtin, K, Salama, M, Atanackovic, D, Niesvizky, R, Landgren, O, Slager, SL, Godley, LA, Churpek, J, Garber, JE, Anderson, KC, Daly, MJ, Roeder, RG, Dumontet, C, Lynch, HT, Mullighan, CG, Camp, NJ, Offit, K, Klein, RJ, Yu, H, Cerchietti, L & Lipkin, SM 2018, 'Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma', Cancer Research, vol. 78, no. 10, pp. 2747-2759. https://doi.org/10.1158/0008-5472.CAN-17-1900
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. / Germline lysine-specific demethylase 1 (lsd1/kdm1a) mutations confer susceptibility to multiple myeloma. In: Cancer Research. 2018 ; Vol. 78, No. 10. pp. 2747-2759.
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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.}",
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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

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