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Repository of Research and Investigative Information

دانشگاه علوم پزشکی و خدمات بهداشتی درمانی زنجان

Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.

(2020) Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells. eLife. ISSN 2050-084X (Electronic)

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Official URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC70396...

Abstract

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics of a conditional knockout mouse, we demonstrate that Kat2a contributes to leukemia propagation through preservation of leukemia stem-like cells. Kat2a loss impacts transcription factor binding and reduces transcriptional burst frequency in a subset of gene promoters, generating enhanced variability of transcript levels. Destabilization of target programs shifts leukemia cell fate out of self-renewal into differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and distinct stages of cancer evolution.

Item Type: Article
Keywords: no keywords
Subjects: QU Biochemistry. Cell Biology and Genetics > QU 300-560 Cell Biology and Genetics
Divisions: Education Vice-Chancellor Department > Faculty of Medicine > Department of Basic Science > Department of Molecular Medicine and Genetics
Journal or Publication Title: eLife
Abstract and Indexing: ISI, Pubmed, Scopus
Quartile : Q1
Volume: 9
Identification Number: https://doi.org/10.7554/eLife.51754
ISSN: 2050-084X (Electronic)
Depositing User: خانم فائزه مظفری
URI: http://repository.zums.ac.ir/id/eprint/7260

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