TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma

Daisuke Ennishi, Shannon Healy, Ali Bashashati, Saeed Saberi, Christoffer Hother, Anja Mottok, Fong Chun Chan, Lauren Chong, Libin Abraham, Robert Kridel, Merrill Boyle, Barbara Meissner, Tomohiro Aoki, Katsuyoshi Takata, Bruce W. Woolcock, Elena Viganò, Michael Gold, Laurie L. Molday, Robert S. Molday, Adele TeleniusMichael Y. Li, Nicole Wretham, Nancy Dos Santos, Mark Wong, Natasja N. Viller, Robert A. Uger, Gerben Duns, Abigail Baticados, Angel Madero, Brianna N. Bristow, Pedro Farinha, Graham W. Slack, Susana Ben-Neriah, Daniel Lai, Allen W. Zhang, Sohrab Salehi, Hennady P. Shulha, Derek S. Chiu, Sara Mostafavi, Alina S. Gerrie, Da Wei Huang, Christopher Rushton, Diego Villa, Laurie H. Sehn, Kerry J. Savage, Andrew J. Mungall, Andrew P. Weng, Marcel B. Bally, Ryan D. Morin, Gabriela V. Cohen Freue, Louis M. Staudt, Joseph M. Connors, Marco A. Marra, Sohrab P. Shah, Randy D. Gascoyne, David W. Scott, Christian Steidl

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and ‘eat-me’ signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation—a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.

Original languageEnglish
Pages (from-to)577-588
Number of pages12
JournalNature Medicine
Volume26
Issue number4
DOIs
Publication statusPublished - Apr 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ennishi, D., Healy, S., Bashashati, A., Saberi, S., Hother, C., Mottok, A., Chan, F. C., Chong, L., Abraham, L., Kridel, R., Boyle, M., Meissner, B., Aoki, T., Takata, K., Woolcock, B. W., Viganò, E., Gold, M., Molday, L. L., Molday, R. S., ... Steidl, C. (2020). TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma. Nature Medicine, 26(4), 577-588. https://doi.org/10.1038/s41591-020-0757-z