title: MCL-1 is required throughout B-cell development and its loss sensitizes specific B-cell subsets to inhibition of BCL-2 or BCL-XL.
abstract: 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.
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Ingela B
authors: IB
authors: Vikström
authors: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors: Anne
authors: A
authors: Slomp
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Emma M
authors: EM
authors: Carrington
authors: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors: Laura M
authors: LM
authors: Moesbergen
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Catherine
authors: C
authors: Chang
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Gemma L
authors: GL
authors: Kelly
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Stefan P
authors: SP
authors: Glaser
authors: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors: J H Marco
authors: JH
authors: Jansen
authors: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors: Jeanette H W
authors: JH
authors: Leusen
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Andreas
authors: A
authors: Strasser
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: David C S
authors: DC
authors: Huang
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: Andrew M
authors: AM
authors: Lew
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.|Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors: Victor
authors: V
authors: Peperzak
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: David M
authors: DM
authors: Tarlinton
mesh_terms: D000818:Animals; D053301:B-Cell Maturation Antigen / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D053301:B-Cell Maturation Antigen; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; C490176:Tnfrsf17 protein, mouse; D051020:bcl-X Protein