期刊
ELIFE
卷 9, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.51754
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资金
- Kay Kendall Leukaemia Fund [KKL888]
- Lady Tata Memorial Trust PhD studentship
- Rosetrees Trust PhD studentship
- Isaac Newton Trust
- H2020 Marie Sklodowska-Curie Actions [800274]
- Wellcome University of Cambridge ISSF
- Wellcome Cambridge/DBT Lectureship
- Associazione Italiana per la Ricerca sul Cancro
- Leuka John Goldman Fellowship for Future Science
- Trinity College, University of Cambridge Henry-Barlow Trust Scholarship
- Cambridge Commonwealth, European & International Trust
- MRC [MC_PC_17230, MR/R009708/1] Funding Source: UKRI
- Marie Curie Actions (MSCA) [800274] Funding Source: Marie Curie Actions (MSCA)
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.
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