Anti-apoptotic A1 is not essential for lymphoma development in Emicro-Myc mice but helps sustain transplanted Emicro-Myc tumour cells
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
WEHI Research Division(s)
Molecular Genetics Of Cancer; Stem Cells And Cancer
PubMed ID
29339775
NHMRC Grants
NHMRC/1016701
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
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