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Loss of signaling via Gα13 in germinal center B cell-derived lymphoma
Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) is a common malignancy yet the signaling pathways deregulated and the factors leading to its systemic dissemination are poorly defined(1,2). Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267955/ https://www.ncbi.nlm.nih.gov/pubmed/25274307 http://dx.doi.org/10.1038/nature13765 |
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author | 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 M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita M. Tubbs, Raymond R. Cook, J. R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. |
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 M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita M. Tubbs, Raymond R. Cook, J. R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. |
author_sort | Muppidi, Jagan R. |
collection | PubMed |
description | Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) is a common malignancy yet the signaling pathways deregulated and the factors leading to its systemic dissemination are poorly defined(1,2). Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of GC B cells(3,4). Recent GCB-DLBCL deep sequencing studies have revealed mutations in a large number of genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2(5-7). 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 GC B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed GC B cell-derived lymphoma. GC B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to GC 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 GC 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 GC B cell-derived malignancy, Burkitt lymphoma (BL), also represses GC 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 GC B cells that is frequently disrupted in GC B cell-derived lymphoma. |
format | Online Article Text |
id | pubmed-4267955 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42679552015-06-11 Loss of signaling via Gα13 in germinal center B cell-derived lymphoma 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 M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita M. Tubbs, Raymond R. Cook, J. R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. Nature Article Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) is a common malignancy yet the signaling pathways deregulated and the factors leading to its systemic dissemination are poorly defined(1,2). Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of GC B cells(3,4). Recent GCB-DLBCL deep sequencing studies have revealed mutations in a large number of genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2(5-7). 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 GC B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed GC B cell-derived lymphoma. GC B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to GC 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 GC 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 GC B cell-derived malignancy, Burkitt lymphoma (BL), also represses GC 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 GC B cells that is frequently disrupted in GC B cell-derived lymphoma. 2014-09-28 2014-12-11 /pmc/articles/PMC4267955/ /pubmed/25274307 http://dx.doi.org/10.1038/nature13765 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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 M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Braziel, Rita M. Tubbs, Raymond R. Cook, J. R. Weisenburger, Dennis D. Chan, Wing C. Vaidehi, Nagarajan Staudt, Louis M. Cyster, Jason G. Loss of signaling via Gα13 in germinal center B cell-derived lymphoma |
title | Loss of signaling via Gα13 in germinal center B cell-derived lymphoma |
title_full | Loss of signaling via Gα13 in germinal center B cell-derived lymphoma |
title_fullStr | Loss of signaling via Gα13 in germinal center B cell-derived lymphoma |
title_full_unstemmed | Loss of signaling via Gα13 in germinal center B cell-derived lymphoma |
title_short | Loss of signaling via Gα13 in germinal center B cell-derived lymphoma |
title_sort | loss of signaling via gα13 in germinal center b cell-derived lymphoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267955/ https://www.ncbi.nlm.nih.gov/pubmed/25274307 http://dx.doi.org/10.1038/nature13765 |
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