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

被引：60

作者：

Ennishi, Daisuke ^{[1
,2
]}

Healy, Shannon ^{[1
]}

Bashashati, Ali ^{[3
]}

Saberi, Saeed ^{[3
]}

Hother, Christoffer ^{[1
]}

Mottok, Anja ^{[1
,4
,5
]}

Chan, Fong Chun ^{[1
,6
]}

Chong, Lauren ^{[1
]}

Abraham, Libin ^{[7
]}

Kridel, Robert ^{[1
]}

Boyle, Merrill ^{[1
]}

Meissner, Barbara ^{[1
]}

Aoki, Tomohiro ^{[1
]}

Takata, Katsuyoshi ^{[1
]}

Woolcock, Bruce W. ^{[1
]}

Vigano, Elena ^{[1
]}

Gold, Michael ^{[7
]}

Molday, Laurie L. ^{[8
]}

Molday, Robert S. ^{[8
]}

Telenius, Adele ^{[1
]}

Li, Michael Y. ^{[1
]}

Wretham, Nicole ^{[9
]}

Dos Santos, Nancy ^{[9
]}

Wong, Mark ^{[10
]}

Viller, Natasja N. ^{[10
]}

Uger, Robert A. ^{[10
]}

Duns, Gerben ^{[1
]}

Baticados, Abigail ^{[1
]}

Madero, Angel ^{[1
]}

Bristow, Brianna N. ^{[1
]}

Farinha, Pedro ^{[1
]}

Slack, Graham W. ^{[1
]}

Ben-Neriah, Susana ^{[1
]}

Lai, Daniel ^{[3
]}

Zhang, Allen W. ^{[3
]}

Salehi, Sohrab ^{[3
]}

Shulha, Hennady P. ^{[1
]}

Chiu, Derek S. ^{[11
]}

Mostafavi, Sara ^{[11
,12
]}

Gerrie, Alina S. ^{[1
]}

Huang, Da Wei ^{[13
]}

Rushton, Christopher ^{[14
]}

Villa, Diego ^{[1
]}

Sehn, Laurie H. ^{[1
]}

Savage, Kerry J. ^{[1
]}

Mungall, Andrew J. ^{[15
]}

Weng, Andrew P. ^{[16
]}

Bally, Marcel B. ^{[9
]}

Morin, Ryan D. ^{[14
,15
]}

Cohen Freue, Gabriela V. ^{[11
]}

机构：

[1] British Columbia Canc, Ctr Lymphoid Canc, Vancouver, BC, Canada

[2] Okayama Univ Hosp, Dept Hematol & Oncol, Okayama, Japan

[3] British Columbia Canc, Mol Oncol, Vancouver, BC, Canada

[4] Ulm Univ, Inst Human Genet, Ulm, Germany

[5] Ulm Univ, Med Ctr, Ulm, Germany

[6] Univ British Columbia, Bioinformat Grad Program, Vancouver, BC, Canada

[7] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC, Canada

[8] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC, Canada

[9] British Columbia Canc, Dept Expt Therapeut, Vancouver, BC, Canada

[10] Trillium Therapeut Inc, Mississauga, ON, Canada

[11] Univ British Columbia, Dept Stat, Vancouver, BC, Canada

[12] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[13] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA

[14] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada

[15] British Columbia Canc, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada

[16] British Columbia Canc, Terry Fox Lab, Vancouver, BC, Canada

[17] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada

来源：

NATURE MEDICINE | 2020年 / 26卷 / 04期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

PHOSPHATIDYLSERINE EXPOSURE; PHOSPHOLIPID FLIPPASES; SIRP-ALPHA; EXPRESSION; RITUXIMAB; RECEPTOR; SIGNAL; CHEMOTHERAPY; P4-ATPASES; MECHANISM;

D O I：

10.1038/s41591-020-0757-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade. 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.

引用

页码：577 / +

页数：29

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