Anti-apoptotic A1 is not essential for lymphoma development in E mu-Myc mice but helps sustain transplanted E mu-Myc tumour cells
AuthorMensink, M; Anstee, NS; Robati, M; Schenk, RL; Herold, MJ; Cory, S; Vandenberg, CJ
Source TitleCell Death and Differentiation
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sVandenberg, Cassandra; Schenk, Robyn; Herold, Marco; Cory, Suzanne; Anstee, Natasha
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsMensink, M., Anstee, N. S., Robati, M., Schenk, R. L., Herold, M. J., Cory, S. & Vandenberg, C. J. (2018). Anti-apoptotic A1 is not essential for lymphoma development in E mu-Myc mice but helps sustain transplanted E mu-Myc tumour cells. CELL DEATH AND DIFFERENTIATION, 25 (4), pp.795-806. https://doi.org/10.1038/s41418-017-0045-8.
Access StatusOpen Access
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 Eµ-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 Eµ-Myc mice and the competitive repopulation capacity of Eµ-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-/- Eµ-Myc lymphomas slowed their expansion, significantly extending the life of the transplant recipients. Thus, A1 contributes to the survival of malignant Eµ-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.
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