Please use this identifier to cite or link to this item:
http://bura.brunel.ac.uk/handle/2438/20318
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Domingues, AF | - |
dc.contributor.author | Kulkarni, R | - |
dc.contributor.author | Giotopoulos, G | - |
dc.contributor.author | Gupta, S | - |
dc.contributor.author | Tan, S | - |
dc.contributor.author | Foerner, E | - |
dc.contributor.author | Adao, RR | - |
dc.contributor.author | Zeka, K | - |
dc.contributor.author | Huntly, BJ | - |
dc.contributor.author | Prabakaran, S | - |
dc.contributor.author | Pina, C | - |
dc.date.accessioned | 2020-02-17T16:05:22Z | - |
dc.date.available | 2018-10-18 | - |
dc.date.available | 2020-02-17T16:05:22Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | bioRxiv, 2018 446096 | en_US |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/20318 | - |
dc.description.abstract | Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective myelo-monocytic 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, we demonstrate that Kat2a contributes to leukemia propagation through homogeneity of transcriptional programs and preservation of leukemia stem-like cells. Kat2a loss reduces transcriptional bursting frequency in a subset of gene promoters, generating enhanced variability of transcript levels but minimal effects on mean gene expression. Destabilization of target programs shifts cellular equilibrium out of self-renewal towards 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 at distinct stages of cancer evolution. | en_US |
dc.description.sponsorship | This work was funded by a Kay Kendall Leukaemia Fund Intermediate Fellowship (KKL888) and by a Leuka John Goldman Fellowship for Future Science (2017) to C.P.. S.P. is funded through a Cambridge-DBT Lectureship; R.K. was funded by an Isaac Newton Trust (INT) Research Grant and a Wellcome Trust ISSF/INT/University of Cambridge Joint Research Grant to C.P.; S.G. is funded by a Lady Tata Memorial Trust PhD Studentship, a Trinity Henry Barlow Trust Scholarship, and the Cambridge Trust; K.Z. received funding from AIRC (Italian Association for Cancer Research) and is the current recipient of a European Commission Horizon 2020 Marie Sklodowska Curie Post-Doctoral Fellowship. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Cold Spring Harbor Laboratory | en_US |
dc.title | Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.1101/446096 | - |
dc.relation.isPartOf | bioRxiv | - |
pubs.publication-status | Published online | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
FullText.pdf | 5.49 MB | Adobe PDF | View/Open |
Items in BURA are protected by copyright, with all rights reserved, unless otherwise indicated.