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Nature. 2014 Dec 11;516(7530):254-8. doi: 10.1038/nature13765. Epub 2014 Sep 28.

Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma.

Author information

1
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.
2
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
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.
4
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
5
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.
6
Department of Pathology, University of Würzburg, 97080 Würzburg, Germany.
7
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.
8
British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
9
Department of Pathology, University of Arizona, Tucson, Arizona 85724, USA.
10
Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.
11
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
12
Pathology Clinic, Rikshospitalet University Hospital, 0372 Oslo, Norway.
13
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.
14
Oregon Health and Science University, Portland, Oregon 97239, USA.
15
Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio 44195, USA.
16
Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.
17
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.

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.

PMID:
25274307
PMCID:
PMC4267955
DOI:
10.1038/nature13765
[Indexed for MEDLINE]
Free PMC Article

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