Anti-apoptotic A1 is not essential for lymphoma development in Emicro-Myc mice but helps sustain transplanted Emicro-Myc tumour cells

Mensink, M; Anstee, NS; Robati, M; Schenk, RL; Herold, MJ; Cory, S; Vandenberg, CJ

Author(s): Mensink, M; Anstee, NS; Robati, M; Schenk, RL; Herold, MJ; Cory, S; Vandenberg, CJ;
Details: Publication Year 2018-03,Volume 25,Issue #4,Page 795-806
Journal Title: Cell Death and Differentiation
Publication Type: Journal Article
Abstract: The transcription factor c-MYC regulates a multiplicity of genes involved in cellular growth, proliferation, metabolism and DNA damage response and its overexpression is a hallmark of many tumours. Since MYC promotes apoptosis under conditions of stress, such as limited availability of nutrients or cytokines, MYC-driven cells are very much dependent on signals that inhibit cell death. Stress signals trigger apoptosis via the pathway regulated by opposing fractions of the BCL-2 protein family and previous genetic studies have shown that the development of B lymphoid tumours in Emicro-Myc mice is critically dependent on expression of pro-survival BCL-2 relatives MCL-1, BCL-W and, to a lesser extent, BCL-XL, but not BCL-2 itself, and that sustained growth of these lymphomas is dependent on MCL-1. Using recently developed mice that lack expression of all three functional pro-survival A1 genes, we show here that the kinetics of lymphoma development in Emicro-Myc mice and the competitive repopulation capacity of Emicro-Myc haemopoietic stem and progenitor cells is unaffected by the absence of A1. However, conditional loss of a single remaining functional A1 gene from transplanted A1-a(-/-)A1-b (fl/fl) A1-c(-/-) Emicro-Myc lymphomas slowed their expansion, significantly extending the life of the transplant recipients. Thus, A1 contributes to the survival of malignant Emicro-Myc-driven B lymphoid cells. These results strengthen the case for BFL-1, the human homologue of A1, being a valid target for drug development for MYC-driven tumours.
Publisher: Springer Nature
Research Division(s): Molecular Genetics Of Cancer; Stem Cells And Cancer
PubMed ID: 29339775
Publisher's Version: https://doi.org/10.1038/s41418-017-0045-8
NHMRC Grants: NHMRC/1016701,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-03-27 09:20:15

Last Modified: 2018-03-27 09:24:25