Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
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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.
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Funder: Isaac Newton Trust; FundRef: http://dx.doi.org/10.13039/501100004815
Funder: Associazione Italiana per la Ricerca sul Cancro; FundRef: http://dx.doi.org/10.13039/501100005010
Funder: Cambridge Commonwealth, European & International Trust; FundRef: http://dx.doi.org/10.13039/501100003343
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Lady Tata Memorial Trust (PhD studentship)
Rosetrees Trust (PhD studentship)
H2020 Marie Skłodowska-Curie Actions (800274)
Wellcome (University of Cambridge ISSF)
Wellcome (Cambridge/DBT Lectureship)
Leuka (John Goldman Fellowship for Future Science)
Trinity College, University of Cambridge (Henry-Barlow Trust Scholarship)