BAK/BAX-Mediated Apoptosis Is a Myc-Induced Roadblock to Reprogramming

Abstract

SummaryDespite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). If MYC is omitted (OKS), reprogramming efficiency is reduced further. Cells must overcome several obstacles to reach the pluripotent state, one of which is apoptosis. To directly determine how extensively apoptosis limits reprogramming, we exploited mouse embryonic fibroblasts (MEFs) lacking the two essential mediators of apoptosis, BAK and BAX. Our results show that reprogramming is enhanced in MEFs deficient in BAK and BAX, but only when MYC is part of the reprogramming cocktail. Thus, the propensity for Myc overexpression to elicit apoptosis creates a significant roadblock to reprogramming under OKSM conditions. Our results suggest that blocking apoptosis during reprogramming may enhance the derivation of iPSCs for research and therapeutic purposes.

Cell Reprogramming in Tumorigenesis and Its Therapeutic Implications for Breast Cancer

“…However, either BYL719 or BH3 mimetic alone does not efficiently suppress estrogen-induced Pik3ca H1047R breast cancer. These results indicate that the anti-apoptosis function of BCL2 family members is important for cell survival during PIK3CA H1047R -induced cell reprogramming toward ER-positive breast cancer, consistent with apoptosis being a barrier for cell reprogramming [56,57]. Therefore, the combined inhibition of anti-apoptosis and cell reprogramming factors may improve the efficacy of anticancer therapy.…”

SuperFreq: Integrated mutation detection and clonal tracking in cancer

“…SuperFreq was designed to detect and track somatic mutations in exomes, and it has been applied to study breast cancer metastasis [2,21], lung cancer xenografts [22], gastric cancer organoids [23], and myeloid leukaemia [24]. SuperFreq is highly versatile and it has since been applied to study small capture sets [25] and low pass whole genomes [26]. We want to draw attention to De Mattos-Arruda [21], where multiple pipelines, including SuperFreq, were used in parallel for clonal tracking, and the authors found overall quite consistent results between methods, providing an independent example of how SuperFreq can be applied for an end-toend analysis on real data.…”

TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition

“…Given that Tfap2c exerts its effects at the initiation phase of the reprogramming, we speculated Tfap2c may promote reprogramming by regulating relevant events involving in this phase. Cell apoptosis has been identified as a barrier to reprogramming 35,50,51 , one of the well-characterized mechanisms is the activation of p53 pathway and the accompanying cell senescence and apoptosis 33,50 . In addition, although c-Myc enhances the overall reprogramming efficiency, c-Myc can also trigger cell apoptosis via p53-dependent and -independent way, which may limit reprogramming 35,50 .…”

“…Given that Tfap2c exerts its effect at the beginning of the reprogramming, a phase which is characterized by the reduction of somatic genes, MET, inhibition of apoptosis and cellular senescence pathways 5,[33][34][35] , we speculated Tfap2c may promote reprogramming by regulating these relevant events. Intriguingly, we observed a significant increased cell number upon Tfap2c overexpression (Fig.…”