| Autor: |
Mensink M; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia.; Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia.; Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands., Anstee NS; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia.; Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia.; Deutsches Krebsforschungszentrum (DKFZ), Experimental Hematology Division, 69120, Heidelberg, Germany., Robati M; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia., Schenk RL; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia.; Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia., Herold MJ; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia.; Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia., Cory S; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia. cory@wehi.edu.au.; Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia. cory@wehi.edu.au., Vandenberg CJ; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia.; Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia. |
| Abstrakt: |
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-X L , 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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