title: 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.
authors: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: G
authors: G
authors: Volpe
authors: D S
authors: DS
authors: Walton
authors: W
authors: W
authors: Del Pozzo
authors: P
authors: P
authors: Garcia
authors: E
authors: E
authors: Dassé
authors: L P
authors: LP
authors: O'Neill
authors: M
authors: M
authors: Griffiths
authors: J
authors: J
authors: Frampton
authors: S
authors: S
authors: Dumon
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D005816:Genetic Complementation Test; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C530718:CEBPA protein, mouse; D018398:Homeodomain Proteins; C000715470:MAS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; C097899:homeobox protein HOXA9; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3