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MCL-1 is required throughout B-cell development and its loss sensitizes specific B-cell subsets to inhibition of BCL-2 or BCL-XL.
Vikström, Ingela B; Slomp, Anne; Carrington, Emma M; Moesbergen, Laura M; Chang, Catherine; Kelly, Gemma L; Glaser, Stefan P; Jansen, J H Marco; Leusen, Jeanette H W; Strasser, Andreas; Huang, David C S; Lew, Andrew M; Peperzak, Victor; Tarlinton, David M.
Afiliación
  • Vikström IB; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • Slomp A; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • Carrington EM; Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
  • Moesbergen LM; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • Chang C; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • Kelly GL; Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
  • Glaser SP; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • Jansen JH; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • Leusen JH; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • Strasser A; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • Huang DC; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • Lew AM; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • Peperzak V; Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
  • Tarlinton DM; Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
Cell Death Dis ; 7(8): e2345, 2016 08 25.
Article en En | MEDLINE | ID: mdl-27560714
Pro-survival BCL-2 family members protect cells from programmed cell death that can be induced by multiple internal or external cues. Within the haematopoietic lineages, the BCL-2 family members BCL-2, BCL-XL and MCL-1 are known to support cell survival but the individual and overlapping roles of these pro-survival BCL-2 proteins for the persistence of individual leukocyte subsets in vivo has not yet been determined. By combining inducible knockout mouse models with the BH3-mimetic compound ABT-737, which inhibits BCL-2, BCL-XL and BCL-W, we found that dependency on MCL-1, BCL-XL or BCL-2 expression changes during B-cell development. We show that BCL-XL expression promotes survival of immature B cells, expression of BCL-2 is important for survival of mature B cells and long-lived plasma cells (PC), and expression of MCL-1 is important for survival throughout B-cell development. These data were confirmed with novel highly specific BH3-mimetic compounds that target either BCL-2, BCL-XL or MCL-1. In addition, we observed that combined inhibition of these pro-survival proteins acts in concert to delete specific B-cell subsets. Reduced expression of MCL-1 further sensitized immature as well as transitional B cells and splenic PC to loss of BCL-XL expression. More markedly, loss of MCL-1 greatly sensitizes PC populations to BCL-2 inhibition using ABT-737, even though the total wild-type PC pool in the spleen is not significantly affected by this drug and the bone marrow (BM) PC population only slightly. Combined loss or inhibition of MCL-1 and BCL-2 reduced the numbers of established PC >100-fold within days. Our data suggest that combination treatment targeting these pro-survival proteins could be advantageous for treatment of antibody-mediated autoimmune diseases and B-cell malignancies.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Linfocitos B / Subgrupos Linfocitarios / Proteína bcl-X / Proteína 1 de la Secuencia de Leucemia de Células Mieloides Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Linfocitos B / Subgrupos Linfocitarios / Proteína bcl-X / Proteína 1 de la Secuencia de Leucemia de Células Mieloides Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Australia