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Acute Leukemias

C/EBPα and MYB regulate FLT3 expression in AML

Abstract

The interaction between the receptor FLT3 (FMS-like tyrosine kinase-3) and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells. Mutation or over-expression of the FLT3 gene, leading to constitutive signalling, enhances the survival and expansion of a variety of leukaemias and is associated with an unfavourable clinical outcome for acute myeloid leukaemia (AML) patients. In this study, we used a murine cellular model for AML and primary leukaemic cells from AML patients to investigate the molecular mechanisms underlying the regulation of FLT3 gene expression and identify its key cis- and trans-regulators. By assessing DNA accessibility and epigenetic markings, we defined regulatory domains in the FLT3 promoter and first intron. These elements permit in vivo binding of several AML-related transcription factors, including the proto-oncogene MYB and the CCAAT/enhancer binding protein C/EBPα, which are recruited to the FLT3 promoter and intronic module, respectively. Substantiating their relevance to the human disease, our analysis of gene expression profiling arrays from AML patients uncovered significant correlations between FLT3 expression level and that of MYB and CEBPA. The latter relationship permits discrimination between patients with CEBPA mono- and bi-allelic mutations, and thus connects two major prognostic factors for AML.

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Acknowledgements

The authors thank the Central England Haemato-oncology Research Biobank for providing the AML patient samples, Robert Slany (Erlangen, Germany) for providing the FMH9 cell line, Toshio Kitamura (Tokyo, Japan) for providing the expression vector for C/EBPα mutants and Roger Bird (Birmingham, UK) for his help with cell sorting. This work was supported by the Leukaemia and Lymphoma Research and the Wellcome Trust.

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Correspondence to S Dumon.

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Volpe, G., Walton, D., Del Pozzo, W. et al. C/EBPα and MYB regulate FLT3 expression in AML. Leukemia 27, 1487–1496 (2013). https://doi.org/10.1038/leu.2013.23

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