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

Mark Mensink, Natasha S. Anstee, Mikara Robati, Robyn L. Schenk, Marco J. Herold, Suzanne Cory, Cassandra J. Vandenberg

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12 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)795-806
Number of pages12
JournalCell Death and Differentiation
Volume25
Issue number4
DOIs
Publication statusPublished - Mar 2018
Externally publishedYes

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