title: Regulation of the Flt3 Gene in Haematopoietic Stem and Early Progenitor Cells.
abstract: The MYB transcription factor plays critical roles in normal and malignant haematopoiesis. We previously showed that MYB was a direct activator of FLT3 expression within the context of acute myeloid leukaemia. During normal haematopoiesis, increasing levels of FLT3 expression determine a strict hierarchy within the haematopoietic stem and early progenitor compartment, which associates with lymphoid and myeloid commitment potential. We use the conditional deletion of the Myb gene to investigate the influence of MYB in Flt3 transcriptional regulation within the haematopoietic stem cell (HSC) hierarchy. In accordance with previous report, in vivo deletion of Myb resulted in rapid biased differentiation of HSC with concomitant loss of proliferation capacity. We find that loss of MYB activity also coincided with decreased FLT3 expression. At the chromatin level, the Flt3 promoter is primed in immature HSC, but occupancy of further intronic elements determines expression. Binding to these locations, MYB and C/EBPα need functional cooperation to activate transcription of the locus. This cooperation is cell context dependent and indicates that MYB and C/EBPα activities are inter-dependent in controlling Flt3 expression to influence lineage commitment of multipotential progenitors.
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Volpe
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Mary
authors.initials: M
authors.lastname: Clarke
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Paloma
authors.initials: P
authors.lastname: Garcìa
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: David Scott
authors.initials: DS
authors.lastname: Walton
authors.affiliation: DKFZ Junior Group Metabolism and Stem Cell Plasticity, Division of Molecular Metabolic Control (A170), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Vegiopoulos
authors.affiliation: School of Physics and Astronomy, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Walter
authors.initials: W
authors.lastname: Del Pozzo
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Laura Patricia
authors.initials: LP
authors.lastname: O'Neill
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Frampton
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dumon
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020626:Oncogene Proteins v-myb / Q000235:genetics / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D020626:Oncogene Proteins v-myb; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3