Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma
Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2014 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/129430 |
| Acesso em linha: | https://hdl.handle.net/2445/129430 |
| Access Level: | acceso abierto |
| Palavra-chave: | Limfomes Limfòcits Transducció de senyal cel·lular Cèl·lules germinals Lymphomas Lymphocytes Cellular signal transduction Germ cells |
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Loss of signalling via Gα13 in germinal center B-cell-derived lymphomaMuppidi, Jagan R.Schmitz, RolandGreen, Jesse A.Xiao, WenmingLarsen, Adrien B.Braun, Sterling E.An, JinpingXu, YingRosenwald, AndreasOtt, GermanGascoyne, Randy D.Rimsza, LisaCampo Güerri, EliasJaffe, Elaine S.Delabie, JanSmeland, Erlend B.Braziel, RitaTubbs, RayCook, James R.Weisenburger, Dennis D.Chan, Wing C.Vaidehi, NagarajanStaudt, Louis M.Cyster, Jason G.LimfomesLimfòcitsTransducció de senyal cel·lularCèl·lules germinalsLymphomasLymphocytesCellular signal transductionGerm cellsGerminal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells3,4. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.Nature Publishing Group2019201920142019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion25 p.application/pdfhttps://hdl.handle.net/2445/129430Articles publicats en revistes (Fonaments Clínics)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1038/nature13765Nature, 2014, vol. 516, num. 7530, p. 254-258https://doi.org/10.1038/nature13765(c) Nature Publishing Group, 2014info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1294302026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| title |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| spellingShingle |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma Muppidi, Jagan R. Limfomes Limfòcits Transducció de senyal cel·lular Cèl·lules germinals Lymphomas Lymphocytes Cellular signal transduction Germ cells |
| title_short |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| title_full |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| title_fullStr |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| title_full_unstemmed |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| title_sort |
Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma |
| dc.creator.none.fl_str_mv |
Muppidi, Jagan R. Schmitz, Roland Green, Jesse A. Xiao, Wenming Larsen, Adrien B. Braun, Sterling E. An, Jinping Xu, Ying Rosenwald, Andreas Ott, German Gascoyne, Randy D. Rimsza, Lisa Campo Güerri, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita Tubbs, Ray Cook, James R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. |
| author |
Muppidi, Jagan R. |
| author_facet |
Muppidi, Jagan R. Schmitz, Roland Green, Jesse A. Xiao, Wenming Larsen, Adrien B. Braun, Sterling E. An, Jinping Xu, Ying Rosenwald, Andreas Ott, German Gascoyne, Randy D. Rimsza, Lisa Campo Güerri, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita Tubbs, Ray Cook, James R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. |
| author_role |
author |
| author2 |
Schmitz, Roland Green, Jesse A. Xiao, Wenming Larsen, Adrien B. Braun, Sterling E. An, Jinping Xu, Ying Rosenwald, Andreas Ott, German Gascoyne, Randy D. Rimsza, Lisa Campo Güerri, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita Tubbs, Ray Cook, James R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Limfomes Limfòcits Transducció de senyal cel·lular Cèl·lules germinals Lymphomas Lymphocytes Cellular signal transduction Germ cells |
| topic |
Limfomes Limfòcits Transducció de senyal cel·lular Cèl·lules germinals Lymphomas Lymphocytes Cellular signal transduction Germ cells |
| description |
Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells3,4. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma. |
| publishDate |
2014 |
| dc.date.none.fl_str_mv |
2014 2019 2019 2019 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/129430 |
| url |
https://hdl.handle.net/2445/129430 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió postprint del document publicat a: https://doi.org/10.1038/nature13765 Nature, 2014, vol. 516, num. 7530, p. 254-258 https://doi.org/10.1038/nature13765 |
| dc.rights.none.fl_str_mv |
(c) Nature Publishing Group, 2014 info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
(c) Nature Publishing Group, 2014 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
25 p. application/pdf |
| dc.publisher.none.fl_str_mv |
Nature Publishing Group |
| publisher.none.fl_str_mv |
Nature Publishing Group |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Fonaments Clínics) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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15,81155 |