Regulation of the Flt3 Gene in Haematopoietic Stem and Early Progenitor Cells.
Regulation of the Flt3 Gene in Haematopoietic Stem and Early Progenitor Cells.
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DOI：
10.1371/journal.pone.0138257
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Dumon S
中科院分区：
文献类型：
--
作者：
Volpe G;Clarke M;Garcìa P;Walton DS;Vegiopoulos A;Del Pozzo W;O'Neill LP;Frampton J;Dumon S
MYB转录因子在正常和恶性造血中起关键作用。我们以前的研究表明，MYB是急性髓系白血病中FLT 3表达的直接激活剂。在正常造血过程中，FLT 3表达水平的增加决定了造血干细胞和早期祖细胞隔室中的严格等级，这与淋巴和骨髓定型潜能有关。我们使用的Myb基因的条件性删除调查的影响，MYB在Flt 3转录调控造血干细胞（HSC）的层次。根据先前的报道，体内Myb的缺失导致HSC的快速偏向分化，伴随着增殖能力的丧失。我们发现MYB活性的丧失也与FLT 3表达的降低相一致。在染色质水平上，Flt 3启动子在未成熟HSC中启动，但其他内含子元件的占据决定表达。MYB和C/EBPα与这些位点结合需要功能上的合作来激活该位点的转录。这种合作是细胞环境依赖性的，表明MYB和C/EBPα活性在控制Flt 3表达以影响多能祖细胞的谱系定型方面是相互依赖的。
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.