An MII-dependent Hox program drives hematopoietic progenitor expansion
An MII-dependent Hox program drives hematopoietic progenitor expansion
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DOI：
10.1016/j.cub.2004.11.012
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发表时间：
2004-11-23
期刊：
影响因子：
9.2
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Ernst, P;Mabon, M;Korsmeyer, SJ
染色体易位破坏混合血统白血病(MII基因导致白血病，伴随一些天然MII靶基因的异常表达(综述于[1])。MII基因编码一种三胸群染色质调节剂，在胚胎发育过程中对造血干细胞(HSCs)的发育至关重要[2]。与Trithorax一样，MLL正向调节聚集性同源结构域或HOX基因，但由于HOX旁系基因之间的冗余，HOX基因在哺乳动物造血系统发育中的共同作用一直难以确定。在这里，我们表明，在缺乏MLL的情况下，尽管HoxA、HoxB和HoxC基因的表达减少，早期造血祖细胞仍会发育。然而，这些祖细胞产生造血祖细胞集落的能力明显降低，这是一个需要细胞分裂和分化的后续过程。在MII缺陷的祖细胞中重新激活HOX基因的一个子集，或者值得注意的是，重新表达单个HOX基因，可以挽救造血祖细胞的频率和生长。相反，表达其他MLL靶基因，如Pitx2或表达抗凋亡的bcl2，未能挽救造血集落频率。此外，我们的结果强调了HOX蛋白在这一点上在造血系统发展中的共同功能。
Chromosomal translocations disrupting the Mixed lineage leukemia (MII gene result in leukemia, with aberrant expression of some native MII target genes (reviewed in [1]). The MII gene encodes a Trithorax-group chromatin regulator that is essential for the development of hematopoietic stem cells (HSCs) during embryogenesis [2]. Like Trithorax, MLL positively regulates clustered homeodomain or Hox genes, yet the role of Hox genes collectively in the development of the mammalian hematopoietic system has been difficult to ascertain because of redundancy among Hox paralogs. Here, we show that in the absence of MLL, early hematopoietic progenitors develop despite reduced expression of HoxA, HoxB, and HoxC genes. However, these progenitors exhibit a marked reduction in their ability to generate hematopoietic colonies, a subsequent process requiring cell division and differentiation. Reactivation of a subset of Hox genes or, remarkably, reexpression of a single Hox gene in MII-deficient progenitors rescued hematopoietic-colony frequency and growth. In contrast, expression of other MLL target genes such as Pitx2 or expression of anti-apoptotic BCL-2 failed to rescue hematopoietic-colony frequency. Furthermore, our results highlight a shared function of Hox proteins at this point in the development of the hematopoietic system.