title: Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma.
abstract: 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 defined. 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 cells. 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.
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Department of Medicine, University of California, San Francisco, California 94143, USA [3] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
authors.forename: Jagan R
authors.initials: JR
authors.lastname: Muppidi
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA [3] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Green
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
authors.forename: Adrien B
authors.initials: AB
authors.lastname: Larsen
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
authors.forename: Sterling E
authors.initials: SE
authors.lastname: Braun
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
authors.forename: Jinping
authors.initials: J
authors.lastname: An
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: 1] Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Auerbachstraße 110, 70376 Stuttgart, Germany [2] Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Department of Pathology, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.affiliation: Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Pathology Clinic, Rikshospitalet University Hospital, 0372 Oslo, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.affiliation: 1] Institute for Cancer Research, Rikshospitalet University Hospital, University of Oslo, 0310 Oslo, Norway [2] Center for Cancer Biomedicine, Faculty Division of the Norwegian Radium Hospital, University of Oslo, 0310 Oslo, Norway.
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.affiliation: Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.affiliation: Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio 44195, USA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.affiliation: Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio 44195, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: 1] Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA [2] Department of Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Vaidehi
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D001769:Blood / Q000276:immunology; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D008196:Lymph / Q000166:cytology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C576600:ARHGEF1 protein, human; C577231:Arhgef1 protein, mouse; C578279:P2RY8 protein, human; D049349:Receptors, Lysosphingolipid; D058470:Receptors, Purinergic P2Y; D064067:Rho Guanine Nucleotide Exchange Factors; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; D051058:Oncogene Protein v-akt; D044365:GTP-Binding Protein alpha Subunits, G12-G13