Regulation of the Flt3 Gene in Haematopoietic Stem and Early Progenitor Cells

• Published in: PloS one Vol. 10; no. 9; p. e0138257
• Main Authors: Volpe, Giacomo, Clarke, Mary, Garcìa, Paloma, Walton, David Scott, Vegiopoulos, Alexandros, Del Pozzo, Walter, O'Neill, Laura Patricia, Frampton, Jonathan, Dumon, Stéphanie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.09.2015; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Animals; Biomedical research; Bone marrow; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - physiology; Cell cycle; Cell Differentiation - genetics; Cell Lineage - genetics; Cells (biology); Cells, Cultured; Chromatin; Clonal deletion; Cooperation; FLT3 gene; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene deletion; Gene expression; Gene Expression Regulation; Gene regulation; Genetic aspects; Genetic regulation; Granulocytes; Hematopoiesis - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Leukemia; Medical research; Mice; Mice, Inbred C57BL; Mice, Transgenic; MYB gene; Oncogene Proteins v-myb - genetics; Oncogene Proteins v-myb - physiology; Physiological aspects; Progenitor cells; Rodents; Stem cells; Transcription factors; United Kingdom; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0138257

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.