WEHI PhD Completion Seminar hosted by Professor Andreas Strasser

Annli Tee

PhD Student – Strasser Laboratory, Blood Cells & Blood Cancer division, WEHI

Examining the distinct and overlapping roles of the different pro-survival BCL-2 family members

 

Davis Auditorium

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Including Q&A session

Apoptosis is vital for embryonic development and tissue homeostasis in adults. Defects in apoptosis can emerge from the overexpression of pro-survival BCL-2 protein family members, and this can give rise to diseases including cancer and autoimmune disorders. BH3-mimetic drugs that inhibit select pro-survival BCL-2 proteins have been developed for cancer therapy. However, whereas the BCL-2 inhibitor Venetoclax is well tolerated in patients, the use of other BH3-mimetics that inhibit related proteins MCL-1 or BCL-XL is more challenging due to on-target toxicity to non-malignant cells, including haematopoietic cells.

We used CRISPR to produce “gene-replacement” mice in which the MCL-1 coding region was replaced with the coding region for BCL-2 (Mcl-1^Bcl-2), BCL-XL (Mcl-1^Bcl-xL) or A1. Remarkably, homozygous Mcl-1^{Bcl-xL/Bcl-xL} and Mcl-1^Bcl-2/Bcl-2 embryos could develop until at least E11.5 on a C57BL/6 background. This demonstrates that only the anti-apoptotic function of MCL-1 – but not its apoptosis-unrelated roles – are essential for early embryogenesis. To examine the impact of replacement of MCL-1 by BCL-XL on hematopoiesis, lethally irradiated mice were reconstituted with Mcl-1^{Bcl-xL/Bcl-xL} hematopoietic stem progenitor cells from E12.5 embryos. Interestingly, the expression of BCL-XL in place of MCL-1 in the hematopoietic system allowed the generation of all blood cell types with a marked increase in platelets and B lymphocytes. Notably, adult heterozygous Mcl-1^wt/Bcl-2 mice showed even more substantial accumulations of B cells and antibody secreting plasma cells in their spleen and bone marrow, and with progressing age they develop SLE-like autoimmune disease similar to what is seen in vav-bcl-2 transgenic mice that overexpress BCL-2. These findings show that distinct pro-survival BCL-2 proteins with their differences in protein stability and interactions with the pro-apoptotic members of the BCL-2 family are best suited to safeguard normal hematopoietic cell survival, with too much pro-survival activity causing disease.

All welcome!