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

Gupta, S.; Dovey, O. M.; Domingues, A. F.; Cyran, O. W.; Cash, C. M.; Giotopoulos, G.; Rak, J.; Cooper, J.; Gozdecka, M.; Asby, R. J.; Al-Jabery, N.; Hernandez-Hernandez, V.; Prabakaran, S.; Huntly, B.; Pina, C.

doi:10.1101/2021.10.18.464824

bioRxiv · 10.1101/2021.10.18.464824

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

Gupta, S.·Dovey, O. M.·Domingues, A. F.·Cyran, O. W.·Cash, C. M.·Giotopoulos, G.·Rak, J.·Cooper, J.·Gozdecka, M.·Asby, R. J.·Al-Jabery, N.·Hernandez-Hernandez, V.·Prabakaran, S.·Huntly, B.·Pina, C.

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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 pre-malignancy to cancer. To investigate this, we initiated pre-leukemia 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 pre-leukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of pre-leukemic 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. In other words, transcriptional variability confers forward momentum to cell fate systems, with differential multi-stage impact throughout cancer evolution. One-sentence summaryLoss of Kat2a enhances transcriptional variability of ribosome biosynthetic programs and transiently accelerates pre-leukemia

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Gupta, S., Dovey, O. M., Domingues, A. F., Cyran, O. W., Cash, C. M., Giotopoulos, G., Rak, J., Cooper, J., Gozdecka, M., Asby, R. J., Al-Jabery, N., Hernandez-Hernandez, V., Prabakaran, S., Huntly, B., Pina, C.. 2021-10-18. Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis. https://doi.org/10.1101/2021.10.18.464824

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