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

作者：Mensink Mark; Anstee Natasha S; Robati Mikara; Schenk Robyn L; Herold Marco J; Cory Suzanne^*; Vandenberg Cassandra J

来源：Cell Death and Differentiation, 2018, 25(4): 795-806.

DOI：10.1038/s41418-017-0045-8

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 E mu-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 E mu-Myc mice and the competitive repopulation capacity of E mu-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(-/-) E mu-Myc lymphomas slowed their expansion, significantly extending the life of the transplant recipients. Thus, A1 contributes to the survival of malignant E mu-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.

• 出版日期2018-3
• 单位河北医科大学