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

Research output: Contribution to journalArticle

Authors

  • Pierre Cauchy
  • David S Walton
  • Daniel Blakemore
  • Rachael Bayley
  • Luisa Schmidt
  • Claus Nerlov
  • Florian Grebien
  • Jon Frampton

External organisations

  • Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK g.volpe@bham.ac.uk.
  • From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.
  • Department of Cellular and Molecular Immunology, Max Planck Institute for Immunobiology and Epigenetics, 79108, Freiburg, Germany.
  • Cancer Bioinfomatics Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
  • Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Institute of Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.
  • Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK j.frampton@bham.ac.uk.

Abstract

Mutations at the N- or C-terminus of C/EBP? 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/EBP? 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/EBP? isoforms, we provide evidence for a functional cooperation between C/EBP? 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/EBP?-regulated genes only bind the short p30 C/EBP? isoform and, unlike other C/EBP?-regulated genes, do so without a requirement for Myb.

Bibliographic note

© 2019 Volpe et al.

Details

Original languageEnglish
Article numbere201800207
JournalLife Science Alliance
Volume2
Issue number2
Early online date15 Mar 2019
Publication statusPublished - 1 Apr 2019