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  Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations

Volpe, G., Cauchy, P., Walton, D. S., Ward, C., Blakemore, D., Bayley, R., et al. (2019). Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations. Life Science Alliance, 2, e201800207. doi:10.26508/lsa.201800207.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-7A54-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-D908-F
Genre: Journal Article

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 Creators:
Volpe, Giacomo1, Author
Cauchy, Pierre2, Author              
Walton, David S.1, Author
Ward, Carl1, Author
Blakemore, Daniel1, Author
Bayley, Rachel1, Author
Clarke, Mary L.1, Author
Schmidt, Luisa1, Author
Nerlov, Claus1, Author
Garcia, Paloma1, Author
Dumon, Stefanie1, Author
Grebien, Florian1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              

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 Abstract: Mutations at the N- or C-terminus of C/EBPα are frequent in acute myeloid leukaemia (AML) with normal karyotype. Here, we investigate the role of the transcription factor Myb in AMLs driven by different combinations of CEBPA mutations. Using knockdown of Myb in murine cell lines modelling the spectrum of CEBPA mutations, we show that the effect of reduced Myb depends on the mutational status of the two Cebpa alleles. Importantly, Myb knockdown fails to override the block in myeloid differentiation in cells with biallelic N-terminal C/EBPα mutations, demonstrating for the first time that the dependency on Myb is much lower in AML with this mutational profile. By comparing gene expression following Myb knockdown and chromatin immunoprecipitation sequencing data for the binding of C/EBPα isoforms, we provide evidence for a functional cooperation between C/EBPα and Myb in the maintenance of AML. This co-dependency breaks down when both alleles of CEBPA harbour N-terminal mutations, as a subset of C/EBPα-regulated genes only bind the short p30 C/EBPα isoform and, unlike other C/EBPα-regulated genes, do so without a requirement for Myb.

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Language(s): eng - English
 Dates: 20192019
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.26508/lsa.201800207
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Title: Life Science Alliance
Source Genre: Journal
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Pages: - Volume / Issue: 2 Sequence Number: - Start / End Page: e201800207 Identifier: -