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http://bura.brunel.ac.uk/handle/2438/25065| Title: | Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis |
| Authors: | Gupta, S Dovey, OM Domingues, AF Cyran, OW Cash, CM Giotopoulos, G Rak, J Cooper, J Gozdecka, M Dijkhuis, L Asby, RJ Al-Jabery, N Hernandez, V Prabakaran, S Huntly, BJ Vassiliou, GS Pina, C |
| Issue Date: | 3-Aug-2022 |
| Publisher: | American Association for the Advancement of Science |
| Citation: | Gupta, S., Dovey, O.M., Domingues, A.F., Cyran, O.W., Cash, C.M., Giotopoulos, G., Rak, J., Cooper, J., Gozdecka, M., Dijkhuis, L., Asby, R.J., Al-Jabery, N., Hernandez, V., Prabakaran, S., Huntly, B.J., Vassiliou, G.S., and Pina, C.. (2022) 'Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis', Science Advances, 8, eabn4886, pp. 1 - 15. doi: 10.1126/sciadv.abn4886. |
| Abstract: | Copyright © 2022 The Authors. 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: | Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. scRNA-seq and bulk RNA-seq data were deposited in ArrayExpress with accession number E-MTAB-10853 and ERP006862, respectively. Code used for single-cell RNA-seq data analysis was deposited in Zenodo and can be accessed as G. Shikha and P. Cristina (2022). scRNA-seq analysis of RUNX1-RUNX1T1(9a) preleukemia, Zenodo; https://doi.org/10.5281/zenodo.6584118. Supplementary Materials: This PDF file includes: Figs. S1 to S7 avilable at: https://www.science.org/doi/suppl/10.1126/sciadv.abn4886/suppl_file/sciadv.abn4886_sm.pdf (223.69 MB). Other Supplementary Material for this manuscript includes the following: Supplementary Files S1 to S9 available at: https://www.science.org/doi/suppl/10.1126/sciadv.abn4886/suppl_file/sciadv.abn4886_supplementary_files_s1_to_s9.zip (2.34 MB). View/request a protocol for this paper from Bio-protocol available at: https://en.bio-protocol.org/cjrap.aspx?eid=10.1126/sciadv.abn4886 |
| URI: | https://bura.brunel.ac.uk/handle/2438/25065 |
| DOI: | https://doi.org/10.1126/sciadv.abn4886 |
| Other Identifiers: | eabn4886 |
| Appears in Collections: | Dept of Life Sciences Research Papers |
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| File | Description | Size | Format | |
|---|---|---|---|---|
| FullText.pdf | 2.29 MB | Adobe PDF | View/Open |
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