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      Contributions of transcriptional noise to leukaemia evolution: KAT2A as a case-study

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          Abstract

          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’.

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          Most cited references151

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          Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

          Timothy Ley, Christopher Miller, Li Ding … (2013)
          Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).
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            Clonal evolution in cancer.

            Mel F Greaves, Carlo C Maley (2012)
            Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.
            Article 0 comments Cited 463 times – based on 0 reviews     Review now
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              Transcriptome-wide noise controls lineage choice in mammalian progenitor cells.

              Hannah Chang, Martin Hemberg, Mauricio Barahona … (2008)
              Phenotypic cell-to-cell variability within clonal populations may be a manifestation of 'gene expression noise', or it may reflect stable phenotypic variants. Such 'non-genetic cell individuality' can arise from the slow fluctuations of protein levels in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous 'outlier' cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise-driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a >200-fold increase in Gata1 (ref. 10) among the erythroid-prone cells, or a >15-fold increased PU.1 (Sfpi1) (ref. 11) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.
              Article 0 comments Cited 401 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Cristina Pina:
                ORCID: http://orcid.org/0000-0002-2575-6301
                Role: ConceptualizationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Journal
                Journal ID (nlm-ta): Philos Trans R Soc Lond B Biol Sci
                Journal ID (iso-abbrev): Philos Trans R Soc Lond B Biol Sci
                Journal ID (publisher-id): RSTB
                Journal ID (hwp): royptb
                Title: Philosophical Transactions of the Royal Society B: Biological Sciences
                Publisher: The Royal Society
                ISSN (Print): 0962-8436
                ISSN (Electronic): 1471-2970
                Publication date (Print, pub): April 22, 2024
                Publication date (Electronic, pub): March 4, 2024
                Publication date PMC-release: March 4, 2024
                Volume: 379
                Issue: 1900 , Discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’ organised and edited by Dagan Jenkins, Jonathan Chubb and Gabriel Galea
                Electronic Location Identifier: 20230052
                Affiliations
                [ 1 ] College of Health, Medicine and Life Sciences, Brunel University London, , Kingston Lane, Uxbridge, London, UB8 3PH, United Kingdom
                [ 2 ] CenGEM – Centre for Genome Engineering and Maintenance, Brunel University London, , Kingston Lane, Uxbridge, London, UB8 3PH, United Kingdom
                Author notes

                One contribution of 10 to a discussion meeting issue ‘ Causes and consequences of stochastic processes in development and disease’.

                Author information
                http://orcid.org/0000-0002-2575-6301
                Article
                Publisher ID: rstb20230052
                DOI: 10.1098/rstb.2023.0052
                PMC ID: 10909511
                PubMed ID: 38432321
                SO-VID: a4490aac-aae9-4b81-b9e0-19c62500f5df
                Copyright © © 2024 The Authors.
                License:

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                Date received : August 1, 2023
                Date accepted : December 4, 2023
                Categories
                Compound subject: 1001
                Compound subject: 58
                Compound subject: 197
                Compound subject: 198
                Subject: Articles
                Subject: Review Articles
                Custom metadata
                cover-date April 22, 2024

                ScienceOpen disciplines: Philosophy of science
                Keywords: transcriptional noise,cell fate decisions,acute myeloid leukaemia,kat2a,ribosomal protein genes
                Data availability:
                ScienceOpen disciplines: Philosophy of science
                Keywords: transcriptional noise, cell fate decisions, acute myeloid leukaemia, kat2a, ribosomal protein genes

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