Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival.
We investigated the mechanism by which B lymphocyte stimulator (BLyS)/BAFF, a tumor necrosis factor superfamily ligand, promotes B-cell survival and resistance to atrophy. BLyS stimulation activates 2 independent signaling pathways, Akt/mTOR and Pim 2, associated with cell growth and survival. BLyS blocks the cell volume loss (atrophy) that freshly isolated B cells normally undergo when maintained in vitro while concurrently increasing glycolytic activity and overall metabolism. This atrophy resistance requires Akt/mTOR. We used a genetic approach to resolve the contributions of Akt/mTOR and Pim kinase pathways to BLyS-mediated survival. Pim 2-deficient B cells are readily protected from death by BLyS stimulation, but this protection is completely abrogated by treatment with the mTOR inhibitor rapamycin. Furthermore, rapamycin treatment in vivo significantly reduces both follicular and marginal zone B cells in Pim-deficient but not healthy hosts. BLyS-dependent survival requires the antiapoptotic protein Mcl-1. Mcl-1 protein levels rise and fall in response to BLyS addition and withdrawal, respectively, and conditional deletion of the Mcl-1 gene renders B cells refractory to BLyS-mediated protection. Because BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could target pathogenic B cells.
Woodland
Robert T
RT
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester 01655, USA. Robert.Woodland@umassmed.edu
Fox
Casey J
CJ
Schmidt
Madelyn R
MR
Hammerman
Peter S
PS
Opferman
Joseph T
JT
Korsmeyer
Stanley J
SJ
Hilbert
David M
DM
Thompson
Craig B
CB
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D053264:B-Cell Activating Factor; D007166:Immunosuppressive Agents; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus