Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma.
(2023) JHEP reports : innovation in hepatology — Vol. 5, n° 10, p. 100838 (2023)
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- Mcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1) on hepatocyte ploidy and cell cycle in murine liver and the possible implications on HCC. Livers of young Mcl-1 and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression . Mcl-1 tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing. In young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1 tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology. Our study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes . In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer. Although Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes , whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation.
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Clerbaux, L.-A., Cordier, P., Desboeufs, N., Unger, K., Leary, P., Semere, G., Boege, Y., Chan, L. K., Desdouets, C., Lopes, M., & Weber, A. (2023). Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma. JHEP reports : innovation in hepatology, 5(10), 100838. https://doi.org/10.1016/j.jhepr.2023.100838 (Original work published 2023)