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

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-bfl/flA1-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.

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…At the molecular levels, resveratrol regulates mitochondrial function via the AMPK‐Mfn1 pathway. AMPK is a pro‐survival signalling in various disease models . For example, AMPK affects Drp1 stabilization and consequently sustains mitochondrial function in diabetic cardiomyopathy.…”

“…AMPK is a pro-survival signalling in various disease models. 43,71 For example, AMPK affects Drp1 stabilization and consequently sustains mitochondrial function in diabetic cardiomyopathy. Besides, in oxidative stress-mediated liver injury, the AMPK pathway could modulate mitochondrial redox balance via CaMKK2 pathway.…”

“…Transfection was performed for approximately 48 hours. Then, Western blotting was used to observe the knockdown efficiency after harvesting the transfected cells …”

Differential effects of Vav‐promoter‐driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis

“…Intriguing differences were observed in the tumour phenotypes. C57BL/6 El-MYC TG mice can develop either pro-/pre-B or B lymphomas [34,45], with the former dominating in our colony. Intriguingly, our El-MYC/Vav-BCLX DT mice developed mainly IgM + B cell lymphomas, like El-MYC mice lacking BIM [45] or BMF [46].…”

“…Using an shRNA-based model to knock down A1 protein expression in mice, we recently observed that MYC-induced lymphomas select against low A1 levels and that diminished A1 renders premalignant cells more susceptible to apoptosis ex vivo [33]. Studies using mice totally lacking A1 also suggest that A1 contributes to tumour cell survival in the context of MYC overexpression [34]. Moreover, the recent report of a patient with DLBCL [35] having a BFL1/ IgH translocation as well as a MYC/IgL translocation suggests that BFL1 overexpression can act as a second hit in MYC-driven B cell lymphomagenesis.…”