Contributions of transcriptional noise to leukaemia evolution: KAT2A as a case-study
Abstract
Data accessibility: This article has no additional data.Declaration of AI use: We have not used AI-assisted technologies in creating this article.Footnotes: One contribution of 10 to a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’ [see: https://doi.org/10.1098/rstb/379/1900].Transcriptional noise is proposed to participate in cell fate changes, but contributions to mammalian cell differentiation systems, including cancer, remain associative. Cancer evolution is driven by genetic variability, with modulatory or contributory participation of epigenetic variants. Accumulation of epigenetic variants enhances transcriptional noise, which can facilitate cancer cell fate transitions. Acute myeloid leukaemia (AML) is an aggressive cancer with strong epigenetic dependencies, characterized by blocked differentiation. It constitutes an attractive model to probe links between transcriptional noise and malignant cell fate regulation. Gcn5/KAT2A is a classical epigenetic transcriptional noise regulator. Its loss increases transcriptional noise and modifies cell fates in stem and AML cells. By reviewing the analysis of KAT2A-depleted pre-leukaemia and leukaemia models, I discuss that the net result of transcriptional noise is diversification of cell fates secondary to alternative transcriptional programmes. Cellular diversification can enable or hinder AML progression, respectively, by differentiation of cell types responsive to mutations, or by maladaptation of leukaemia stem cells. KAT2A-dependent noise-responsive genes participate in ribosome biogenesis and KAT2A loss destabilizes translational activity. I discuss putative contributions of perturbed translation to AML biology, and propose KAT2A loss as a model for mechanistic integration of transcriptional and translational control of noise and fate decisions. This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.No specific funding for this study. Work in the Pina lab is funded by the Lady Tata Memorial Trust, by the Little Princess Trust through the Children’s Cancer and Leukaemia Group, and by an MRC Pilot Scheme / Brunel University London Research Development Fund awardSimilar works
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This paper was published in Brunel University Research Archive.
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