Regulation of the Flt3 Gene in Haematopoietic Stem and Early Progenitor Cells
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 hiera...
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Published in | PloS one Vol. 10; no. 9; p. e0138257 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
18.09.2015
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: SD JF. Performed the experiments: GV SD MC PG DSW AV. Analyzed the data: SD GV MC PG DSW AV. Contributed reagents/materials/analysis tools: WDP LPON. Wrote the paper: SD GV JF. These authors are joint senior authors. |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0138257 |