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http://bura.brunel.ac.uk/handle/2438/20199
Title: | Loss of Kat2a Enhances Transcriptional Noise and depletes Acute Myeloid Leukaemia Stem-like Cells |
Authors: | Domingues, AF Kulkarni, R Giotopoulos, G Gupta, S Vinnenberg, L Arede, L Foerner, E Khalili, M Romano Adao, R Johns, A Tan, S Zeka, K Huntly, BJ Prabakaran, S Pina, C |
Issue Date: | 27-Jan-2020 |
Publisher: | eLife Sciences Publications |
Citation: | Domingues, A.F., Kulkarni, R., Giotopoulos, G., Gupta, S., Vinnenberg, L., Arede, L., Foerner, E., Khalili, M., Adao, R.R., Johns, A. and Tan, S. (2020) 'Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells', Elife, 9, e51754, pp. 1-29. doi: 10.7554/eLife.51754. |
Abstract: | © 2020, Domingues et al. 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. |
URI: | https://bura.brunel.ac.uk/handle/2438/20199 |
DOI: | https://doi.org/10.7554/eLife.51754 |
Other Identifiers: | e51754 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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