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

Published version
Peer-reviewed

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Authors

Domingues, Ana Filipa 
Kulkarni, Rashmi 
Giotopoulos, George 
Gupta, Shikha 
Vinnenberg, Laura 

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.

Description

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

Keywords

Research Article, Cancer Biology, Chromosomes and Gene Expression, acute myeloid leukaemia, transcriptional heterogeneity, epigenetics, Kat2a, Single-cell RNA seq, transcriptional bursting, Mouse

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X

Volume Title

9

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Kay Kendall Leukaemia Fund (KKL888)
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)