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Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma
- Source :
- Nature. December 11, 2014, Vol. 516 Issue 7530, p254, 18 p.
- Publication Year :
- 2014
-
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 (1,2). Work in mice showed that sphingosine-l-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells (3,4). Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5-7). Here we show, using in vitro and in vivo assays, that GCBDLBCL-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.<br />We sequenced the S1PR2 coding region in 117 GCB-DLBCL, 31 Burkitt's lymphoma and 68 activated B-cell-like (ABC)-DLBCL samples. Twelve S1PR2 coding mutations were identified in the GCB-DLBCL samples versus one [...]
Details
- Language :
- English
- ISSN :
- 00280836
- Volume :
- 516
- Issue :
- 7530
- Database :
- Gale General OneFile
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.393352915