1. TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma.
- Author
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Ennishi D, Healy S, Bashashati A, Saberi S, Hother C, Mottok A, Chan FC, Chong L, Abraham L, Kridel R, Boyle M, Meissner B, Aoki T, Takata K, Woolcock BW, Viganò E, Gold M, Molday LL, Molday RS, Telenius A, Li MY, Wretham N, Dos Santos N, Wong M, Viller NN, Uger RA, Duns G, Baticados A, Madero A, Bristow BN, Farinha P, Slack GW, Ben-Neriah S, Lai D, Zhang AW, Salehi S, Shulha HP, Chiu DS, Mostafavi S, Gerrie AS, Huang DW, Rushton C, Villa D, Sehn LH, Savage KJ, Mungall AJ, Weng AP, Bally MB, Morin RD, Cohen Freue GV, Staudt LM, Connors JM, Marra MA, Shah SP, Gascoyne RD, Scott DW, and Steidl C
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, British Columbia epidemiology, Cells, Cultured, Cohort Studies, Female, Genetic Predisposition to Disease, HEK293 Cells, Humans, Jurkat Cells, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Middle Aged, Young Adult, Cell Transformation, Neoplastic genetics, Loss of Function Mutation genetics, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse therapy, Membrane Proteins genetics, Molecular Targeted Therapy methods, Molecular Targeted Therapy trends
- 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.
- Published
- 2020
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