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

Ingela B Vikstrom, Anne Slomp, Emma M Carrington, Laura M Moesbergen, Catherine Chang, Gemma L. Kelly, Stefan P Glaser, J H Marco Jansen, Jeanette H W Leusen, Andreas Strasser, David C S Huang, Andrew M Lew, Victor Peperzak, David M Tarlinton

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25 Citations (Scopus)

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.

Original languageEnglish
Article numbere2345
JournalCell Death and Disease
Volume7
Issue number8
DOIs
Publication statusPublished - 25 Aug 2016
Externally publishedYes

Cite this

Vikstrom, I. B., Slomp, A., Carrington, E. M., Moesbergen, L. M., Chang, C., Kelly, G. L., Glaser, S. P., Jansen, J. H. M., Leusen, J. H. W., Strasser, A., Huang, D. C. S., Lew, A. M., Peperzak, V., & Tarlinton, D. M. (2016). MCL-1 is required throughout B-cell development and its loss sensitizes specific B-cell subsets to inhibition of BCL-2 or BCL-XL. Cell Death and Disease, 7(8), [e2345]. https://doi.org/10.1038/cddis.2016.237