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

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

doi:10.1038/s41591-020-0757-z

Cited by 51 publications

(60 citation statements)

References 51 publications

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“…We assessed the overall survival of patients within GCB-DLBCL or EZB with or without FAS ALTs in a combined cohort of patients from two centers who had been classified into gene expression and genetic subtypes with paired gene expression data (NCI and British Columbia Cancer [BCC] cohorts; Ennishi et al, 2019 , 2020 ; Schmitz et al, 2018 ; Wright et al, 2020 ). In both GCB-DLBCL and EZB, loss of FAS was associated with worse outcomes compared with patients with WT FAS ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A schematic of FAS mutation locations was generated with ProteinPaint ( https://pecan.stjude.cloud/proteinpaint ). Overall survival and the landscape of genetic alterations in EZB cases were assessed in the NCI cohort and the BCC cohort ( Ennishi et al, 2019 , 2020 ). The depleted LME signature was recently described ( Cerchietti et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

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Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma

Razzaghi

Agarwal

Kotlov

et al. 2020

Journal of Experimental Medicine

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Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell–derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh–B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma

Razzaghi

Agarwal

Kotlov

et al. 2020

Journal of Experimental Medicine

Self Cite

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“…11 To our knowledge, TMEM30A mutations have not been reported in association with sarcomas; however, they are present in approximately 5% of diffuse large B-cell lymphomas. 12…”

Section: Case Reportmentioning

confidence: 99%

Sclerosing Epithelioid Fibrosarcoma of the Kidney: First Reported Case in a Young Child

2021

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Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma primarily arising in the deep soft tissue of the extremities and trunk. Despite having the morphologic appearance of a low-grade sarcoma, it generally has an aggressive clinical course with frequent local recurrences and distant metastases. It typically occurs in middle aged adults and is characterized by immunoexpression of MUC4 and recurrent gene fusions, most commonly EWSR1-CREB3L1. We report a primary renal SEF in a 4-year-old male. To our knowledge, this is the youngest patient reported with SEF and the second case of SEF in a pre-adolescent child. It is the eleventh reported case of primary renal SEF in the literature. While SEF arising in visceral organs is rare, the kidney is the most common primary site of any visceral organ. This case demonstrates SEF can occur in pre-adolescents, is an important consideration when evaluating sarcomas in young children, and should be considered in the differential diagnosis for primary renal tumors.

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“…In erythrocytes, CD47 ligation induces PS expression as part of a death pathway 191 , suggesting that CD47 could affect PS exposure. Indeed, knockout of CDC50A, a subunit of ATP11C that participates in PS flipping, increases tumor-associated macrophages and enhances the effect of anti-CD47 blockade on limiting tumor growth 192 . Knockout of CDC50A also increases PS exposure on Jurkat cells, which may affect T cell function, as we mentioned earlier.…”

Section: Ps Exposure and Cd47 For Cancer Therapymentioning

confidence: 99%

Targeting phosphatidylserine for Cancer therapy: prospects and challenges

Chang

Xiao

et al. 2020

Theranostics

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Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved tumor elimination are still lacking. Recently, immunotherapy has attracted much attention, and many immune-active agents have been approved for clinical use alone or in combination with other cancer drugs. However, some patients have a poor response to these agents. New agents and strategies are needed to overcome such deficiencies. Phosphatidylserine (PS) is an essential component of bilayer cell membranes and is normally present in the inner leaflet. In the physiological state, PS exposure on the external leaflet not only acts as an engulfment signal for phagocytosis in apoptotic cells but also participates in blood coagulation, myoblast fusion and immune regulation in nonapoptotic cells. In the tumor microenvironment, PS exposure is significantly increased on the surface of tumor cells or tumor cell-derived microvesicles, which have innate immunosuppressive properties and facilitate tumor growth and metastasis. To date, agents targeting PS have been developed, some of which are under investigation in clinical trials as combination drugs for various cancers. However, controversial results are emerging in laboratory research as well as in clinical trials, and the efficiency of PS-targeting agents remains uncertain. In this review, we summarize recent progress in our understanding of the physiological and pathological roles of PS, with a focus on immune suppressive features. In addition, we discuss current drug developments that are based on PS-targeting strategies in both experimental and clinical studies. We hope to provide a future research direction for the development of new agents for cancer therapy.

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

Cited by 51 publications

References 51 publications

Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma

Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma

Sclerosing Epithelioid Fibrosarcoma of the Kidney: First Reported Case in a Young Child

Targeting phosphatidylserine for Cancer therapy: prospects and challenges

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