HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development
HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development
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DOI：
10.1182/blood-2006-10-054676
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Karlsson, Stefan
中科院分区：
文献类型：
--
作者：
Magnusson, Mattias;Brun, Ann C. M.;Karlsson, Stefan
同源盒（Hox）转录因子是正常和恶性造血的重要调节因子，因为它们控制造血系统不同级别的造血细胞的增殖、分化和自我更新。在转基因小鼠中，我们发现 HOXA10 的表达受到多西环素的严格调节。体外培养 13 天后，中等浓度的 HOXA10 诱导造血干细胞 (HSC) 的再生能力增加 15 倍。值得注意的是，HOXA10对HSC增殖的诱导作用取决于HOXA10的浓度，因为高水平的HOXA10对HSC增殖没有影响。此外，高水平的 HOXA10 阻碍红细胞和巨核细胞发育，表明 HOXA10 的严格调节对于红细胞和巨核细胞谱系的正常发育至关重要。 HOXA10介导的对造血细胞的影响与控制干细胞自我更新和谱系定型的基因（例如肝白血病因子[HlF]、Dickkopf-1 [Dkk-1]、生长因子独立-1 [Cfl-1]和Gata-1）的表达改变有关。有趣的是，在 HLF、Dkk-1 和 Gata-1 中发现了 HOXA10 的结合位点，并且 Dkk-1 和 Gfl-1 被 HOXA10 转录激活。这些发现揭示了作用于 HOXA10 下游的新分子途径，并将 HOXA10 确定为出生后造血发育的主要调节因子。 (C) 2007 年，美国血液学会。
The Homeobox (Hox) transcription factors are important regulators of normal and malignant hematopoiesis because they control proliferation, differentiation, and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. In transgenic mice we show that the expression of HOXA10 is tightly regulated by doxycycline. Intermediate concentrations of HOXA10 induced a 15-fold increase in the repopulating capacity of hematopoietic stem cells (HSCs) after 13 days of in vitro culture. Notably, the proliferation induction of HSC by HOXA10 was dependent on the HOXA10 concentration, because high levels of HOXA10 had no effect on HSC proliferation. Furthermore, high levels of HOXA10 blocked erythroid and megakaryocyte development, demonstrating that tight regulation of HOXA10 is critical for normal development of the erythroid and megakaryocytic lineages. The HOXA10-mediated effects on hematopoietic cells were associated with altered expression of genes that govern stem-cell self-renewal and lineage commitment (eg, hepatic leukemia factor [HlF], Dickkopf-1 [Dkk-1], growth factor independent-1 [Cfl-1], and Gata-1). Interestingly, binding sites for HOXA10 were found in HLF, Dkk-1, and Gata-1, and Dkk-1 and Gfl-1 were transcriptionally activated by HOXA10. These findings reveal novel molecular pathways that act downstream of HOXA10 and identify HOXA10 as a master regulator of postnatal hematopoietic development. (C) 2007 by The American Society of Hematology.