Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.
J Biol Chem. 2011 May 27;286(21):19047-64. doi: 10.1074/jbc.M110.213983. Epub 2011 Apr 6.
HoxA10 is a homeodomain transcription factor that influences a number of developmental processes, including hematopoiesis. During definitive hematopoiesis, expression of HoxA10 is maximal in committed myeloid progenitor cells and decreases as differentiation proceeds. Aberrantly increased expression of HoxA10 was found in bone marrow cells in a poor prognosis subset of human acute myeloid leukemia (AML). Consistent with this, AML developed in mice transplanted with HoxA10-overexpressing bone marrow. However, relatively few target genes have been identified that explain the role of HoxA10 in leukemogenesis. In the current study, we identified CDX4 as a HoxA10 target gene. Cdx4 is a homeodomain transcription factor that was also implicated in myeloid leukemogenesis. Although relatively few Cdx4 target genes have been identified, Cdx4 was known to influence HOX gene transcription. We identified a HoxA10-binding cis element in the CDX4 promoter that activated transcription. We also identified a Cdx4-binding cis element that activated the HOXA10 promoter. Therefore, increased Cdx4 expression in HoxA10-overexpressing cells augmented transcription of the endogenous HOXA10 gene. Increased endogenous HoxA10 in these cells induced additional CDX4 transcription. We found that Cdx4 influenced transcription of HoxA10 target genes in a HoxA10-dependent manner. Similarly, HoxA10 influenced transcription of HOX genes in a Cdx4-dependent manner. We previously found that HoxA10-overexpressing myeloid progenitors were hypersensitive to a variety of cytokines. In the current studies, we found that Cdx4 knockdown decreased cytokine hypersensitivity of HoxA10-overexpressing cells. Therefore, these studies identified a positive feedback relationship between HoxA10 and Cdx4, which potentially amplified the contribution of either transcription factor to the pathogenesis of AML.
HoxA10 是一种同源域转录因子，它影响许多发育过程，包括造血。在确定性造血过程中，HoxA10 的表达在定向髓系祖细胞中最大，并随着分化的进行而降低。在人类急性髓系白血病（AML）预后不良亚组的骨髓细胞中发现 HoxA10 的表达异常增加。与此一致的是，用过表达 HoxA10 的骨髓移植的小鼠中发展出 AML。然而，相对较少的靶基因被鉴定出来，解释了 HoxA10 在白血病发生中的作用。在本研究中，我们确定 CDX4 是 HoxA10 的一个靶基因。Cdx4 是一种同源域转录因子，也涉及髓系白血病的发生。尽管相对较少的 Cdx4 靶基因被鉴定出来，但 Cdx4 被认为影响 HOX 基因的转录。我们在 CDX4 启动子中鉴定出一个 HoxA10 结合顺式元件，该元件激活转录。我们还鉴定出一个 Cdx4 结合顺式元件，该元件激活 HOXA10 启动子。因此，在过表达 HoxA10 的细胞中增加 Cdx4 表达增强了内源性 HOXA10 基因的转录。这些细胞中内源性 HoxA10 的增加诱导了额外的 CDX4 转录。我们发现 Cdx4 以 HoxA10 依赖的方式影响 HoxA10 靶基因的转录。同样，HoxA10 以 Cdx4 依赖的方式影响 HOX 基因的转录。我们之前发现过表达 HoxA10 的髓系祖细胞对各种细胞因子敏感。在目前的研究中，我们发现 Cdx4 的敲低降低了过表达 HoxA10 的细胞对细胞因子的敏感性。因此，这些研究确定了 HoxA10 和 Cdx4 之间的正反馈关系，这可能放大了任一转录因子对 AML 发病机制的贡献。
