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Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis

Published version
Peer-reviewed

Type

Article

Change log

Authors

Dovey, Oliver M 
Domingues, Ana Filipa  ORCID logo  https://orcid.org/0000-0003-3062-9144
Cyran, Oliwia W 
Cash, Caitlin M 

Abstract

Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this, we initiated preleukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA sequencing of preleukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of preleukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. That is, transcriptional variability confers forward momentum to cell fate systems, with differential multistage impact throughout cancer evolution.

Description

Keywords

Animals, Cell Differentiation, Leukemia, Mice, Preleukemia, Protein Biosynthesis

Journal Title

Science Advances

Conference Name

Journal ISSN

2375-2548
2375-2548

Volume Title

8

Publisher

American Association for the Advancement of Science
Sponsorship
European Research Council (647685)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (23015)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_PC_17230)
Cancer Research UK (25508)