Loss of signalling via G α 13 in germinal centre B-cell-derived lymphoma

Jagan R. Muppidi, Roland Schmitz, Jesse A. Green, Wenming Xiao, Adrien B. Larsen, Sterling E. Braun, Jinping An, Ying Xu, Andreas Rosenwald, German Ott, Randy D. Gascoyne, Lisa M. Rimsza, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Rita M. Braziel, Raymond R. Tubbs, J. R. Cook, Dennis D. WeisenburgerWing C. Chan, Nagarajan Vaidehi, Louis M. Staudt, Jason G. Cyster

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Germinal centre B-cell-like diffuse largeB-cell lymphoma(GCB-DLBCL) is a commonmalignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2.Workinmice showedthat sphingosine-1-phosphate receptor-2 (S1PR2), aGa12 andGa13 coupled receptor, promotes growth regulation andlocal confinement of germinal centreBcells3,4.Recent deep sequencing studies ofGCB-DLBCL have revealedmutations inmany genes in this cancer, including inGNA13 (encodingGa13) andS1PR2 (refs 5-7). Here weshow, usingin vitro andin vivo assays, thatGCBDLBCL-associatedmutations occurring in S1PR2frequentlydisrupt the receptor'sAkt andmigration inhibitory functions.Ga13-deficient mouse germinal centre B cells and humanGCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Ga13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centreBcells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency inGa13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood.GCB-DLBCL cell lines frequently carriedmutations in theGa13 effectorARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Ga13-and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derivedmalignancy,Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Ga13.These findings identify aGa13-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.

Original languageEnglish (US)
Pages (from-to)254-258
Number of pages5
JournalNature
Volume516
Issue number7530
DOIs
StatePublished - Dec 11 2014

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    Muppidi, J. R., Schmitz, R., Green, J. A., Xiao, W., Larsen, A. B., Braun, S. E., An, J., Xu, Y., Rosenwald, A., Ott, G., Gascoyne, R. D., Rimsza, L. M., Campo, E., Jaffe, E. S., Delabie, J., Smeland, E. B., Braziel, R. M., Tubbs, R. R., Cook, J. R., ... Cyster, J. G. (2014). Loss of signalling via G α 13 in germinal centre B-cell-derived lymphoma. Nature, 516(7530), 254-258. https://doi.org/10.1038/nature13765