MCL-1 is required throughout B-cell development and its loss sensitizes specific B-cell subsets to inhibition of BCL-2 or BCL-XL

Vikstrom, IB; Slomp, A; Carrington, EM; Moesbergen, LM; Chang, C; Kelly, GL; Glaser, SP; Jansen, JH; Leusen, JH; Strasser, A; Huang, DC; Lew, AM; Peperzak, V; Tarlinton, DM

Author(s): Vikstrom, IB; Slomp, A; Carrington, EM; Moesbergen, LM; Chang, C; Kelly, GL; Glaser, SP; Jansen, JH; Leusen, JH; Strasser, A; Huang, DC; Lew, AM; Peperzak, V; Tarlinton, DM;
Details: Publication Year 2016,Volume 7,Issue #8,Page e2345
Journal Title: Cell Death Dis
Publication Type: Journal Article
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.
Publisher: SPRINGER NATURE
Research Division(s): Immunology; Molecular Genetics Of Cancer; Cancer And Haematology
PubMed ID: 27560714
Publisher's Version: https://doi.org/10.1038/cddis.2016.237
Open Access at Publisher's Site: www.nature.com/cddis/journal/v7/n8/full/cddis2016237a.html
NHMRC Grants: NHMRC/1021374, NHMRC/356202, NHMRC/637326, NHMRC/1016701, NHMRC/1020363, NHMRC/1043414, NHMRC/1037321,
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Creation Date: 2016-10-03 03:38:09

Last Modified: 2016-10-03 04:56:47