The Walter and Eliza Hall Institute of Medical Research, Victoria, 3052, Australia.
Department of Medical Biology, University of Melbourne, Victoria, 3052, Australia.
Cell Death Differ. 2018 Mar;25(4):797-808. doi: 10.1038/s41418-017-0045-8. Epub 2018 Jan 16.
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, 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-aA1-b 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.
转录因子 c-MYC 调节多种参与细胞生长、增殖、代谢和 DNA 损伤反应的基因，其过度表达是许多肿瘤的标志。由于 MYC 在应激条件下促进细胞凋亡，例如营养物质或细胞因子供应有限，因此 MYC 驱动的细胞非常依赖于抑制细胞死亡的信号。应激信号通过 BCL-2 蛋白家族的对立分数调节的途径触发细胞凋亡，先前的遗传研究表明，Eµ-Myc 小鼠中 B 淋巴细胞瘤的发展严重依赖于生存 BCL-2 相关蛋白 MCL-1、BCL-W 和在较小程度上依赖于 BCL-X 的表达，但不依赖于 BCL-2 本身，并且这些淋巴瘤的持续生长依赖于 MCL-1。使用最近开发的缺乏所有三种功能性生存 A1 基因表达的小鼠，我们在这里表明，Eµ-Myc 小鼠中淋巴瘤的发展动力学和 Eµ-Myc 造血干/祖细胞的竞争再殖能力不受 A1 缺失的影响。然而，从移植的 A1-aA1-b A1-c Eµ-Myc 淋巴瘤中条件性缺失单个剩余的功能性 A1 基因会减缓其扩张速度，显著延长移植受体的寿命。因此，A1 有助于恶性 Eµ-Myc 驱动的 B 淋巴细胞瘤细胞的存活。这些结果为 BFL-1（A1 的人类同源物）作为 MYC 驱动肿瘤药物开发的有效靶点提供了更有力的证据。
