@article{b54137202eb843a8bf46418f2b9d35b0,
title = "TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma",
abstract = "Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and {\textquoteleft}eat-me{\textquoteright} 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.",
author = "Daisuke Ennishi and Shannon Healy and Ali Bashashati and Saeed Saberi and Christoffer Hother and Anja Mottok and Chan, {Fong Chun} and Lauren Chong and Libin Abraham and Robert Kridel and Merrill Boyle and Barbara Meissner and Tomohiro Aoki and Katsuyoshi Takata and Woolcock, {Bruce W.} and Elena Vigan{\`o} and Michael Gold and Molday, {Laurie L.} and Molday, {Robert S.} and Adele Telenius and Li, {Michael Y.} and Nicole Wretham and {Dos Santos}, Nancy and Mark Wong and Viller, {Natasja N.} and Uger, {Robert A.} and Gerben Duns and Abigail Baticados and Angel Madero and Bristow, {Brianna N.} and Pedro Farinha and Slack, {Graham W.} and Susana Ben-Neriah and Daniel Lai and Zhang, {Allen W.} and Sohrab Salehi and Shulha, {Hennady P.} and Chiu, {Derek S.} and Sara Mostafavi and Gerrie, {Alina S.} and Huang, {Da Wei} and Christopher Rushton and Diego Villa and Sehn, {Laurie H.} and Savage, {Kerry J.} and Mungall, {Andrew J.} and Weng, {Andrew P.} and Bally, {Marcel B.} and Morin, {Ryan D.} and {Cohen Freue}, {Gabriela V.} and Staudt, {Louis M.} and Connors, {Joseph M.} and Marra, {Marco A.} and Shah, {Sohrab P.} and Gascoyne, {Randy D.} and Scott, {David W.} and Christian Steidl",
note = "Funding Information: This study was supported by a Program Project Grant from the Terry Fox Research Institute (R.D.G, grant no. 1023; C.S., grant no. 1061), a Large Scale Applied Research Project (LSARP) from Genome Canada (C.S., grant no. 13124), Genome British Columbia (C.S., 271LYM), Canadian Institutes of Health Research (CIHR) (C.S., GP1-155873) and the British Columbia Cancer Foundation (BCCF). D.E. was supported by fellowships from the Michael Smith Foundation for Health Research (MSFHR), Canadian Institutes of Health Research (CIHR) and Japanese Society for The Promotion of Science. D.W.S. is supported by the British Columbia Cancer Foundation (BCCF) and the Michael Smith Foundation for Health Research (MSFHR). J.M.C. was the Clinical Director of the British Columbia Cancer Agency Centre for Lymphoid Cancer and received research funding support from the Terry Fox Research Institute, Genome Canada, Genome British Columbia, CIHR and the BCCF. C.H. was supported by the Alfred Benzon foundation. A.M. is supported by fellowships from the Mildred-Scheel-Cancer-Foundation (German Cancer Aid), the MSFHR and Lymphoma Canada. E.V. is supported by a fellowship from the Michael Smith Foundation for Health Research. G.V.C.F is supported by an NSERC Discovery grant. R.D.M. is funded by a CIHR New Investigator Award. M.A.M. is UBC Canada Research Chair in Genome Science and is pleased to acknowledge support from CIHR (FDN-143288) and the Terry Fox Research Institute. S.P.S. holds the Canada Research Chair in Computational Cancer Genomics, is a MSFHR scholar, holds a CIHR Foundation grant and acknowledges support from the BCCF. T.A. was supported by the Japanese Society for the Promotion of Science and the Uehara Memorial Foundation. T.A. received research funding support from The Kanae Foundation for the Promotion of Medical Science. L.A., as well as the experiments carried out by L.A., were supported by CIHR grant PJT-152946 (to M.R.G.). R.S.M holds a Canada Research Chair in Vision and Macular Degeneration and acknowledges support from CIHR (PJT-148649). K.T. was supported by fellowships from the Uehara Memorial Foundation. We thank E. Toombs for assistance in performing research, analyzing and interpreting data. Funding Information: D.W.S., J.M.C. and R.D.G. are inventors on a patent held by the National Cancer Institute that has been licensed by NanoString Technologies. C.S. has performed consultancy for Seattle Genetics, Curis Inc., Roche, AbbVie, Juno Therapeutics and Bayer, and has received research funding from Bristol-Myers Squibb and Trillium Therapeutics Inc. D.W.S. has performed consultancy for Janssen and Celgene and has received research funding from Roche/Genentech, Janssen and NanoString Technologies. R.D.G. has performed consultancy for Celgene. R.K. received travel support from Roche. D.V., A.S.G, K.J.S., J.M.C., L.H.S. and D.W.S. received institutional research funding from Roche. L.H.S. has performed consultancy and received honoraria from Amgen, Abbvie, Apobiologix, Celgene, Lundbeck, Janssen, Karyopharm, TG Therapeutics, Roche/Genentech, Teva and Takeda. K.J.S. received honoraria and provided consultancy to Bristol-Myers Squibb, Merck, Takeda, Verastem and Servier. A.S.G. received honoraria and provided consultancy to Janssen, AbbVie and Seattle Genetics. D.V. received honoraria from and participated in advisory boards for: Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen and Gilead. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = apr,
day = "1",
doi = "10.1038/s41591-020-0757-z",
language = "English",
volume = "26",
pages = "577--588",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}
