The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis
The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis
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DOI：
10.1172/jci30182
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Froehling, Stefan
中科院分区：
文献类型：
--
作者：
Scholl, Claudia;Bansal, Dimple;Froehling, Stefan
同源异型盒转录因子CDX 2在胚胎发育中起重要作用，并调节成年肠上皮细胞的增殖和分化。我们已经发现，CDX 2在90%的急性髓性白血病（AML）患者的白血病细胞中表达，但在来自正常个体的造血干细胞和祖细胞中不表达。通过RNA干扰稳定敲低CDX 2表达抑制了各种人AML细胞系的增殖，并大大降低了其体外克隆形成潜力。用Cdx 2转导的原代小鼠造血祖细胞获得了连续再铺板活性，能够在液体培养中连续繁殖，在BM移植受体中产生完全渗透和可移植的AML，并在体外和体内显示Hox家族成员的表达失调。这些结果表明，发育调控基因CDX 2在成人造血区室中的异常表达是AML发病机制中的常见事件;表明CDX 2作为促进骨髓祖细胞增殖能力和自我更新潜力的常见效应子途径的一部分的作用;并支持CDX 2部分负责在大多数AML病例中观察到的HOX基因表达改变的假设。
The homeobox transcription factor CDX2 plays an important role in embryonic development and regulates the proliferation and differentiation of intestinal epithelial cells in the adult. We have found that CDX2 is expressed in leukemic cells of 90% of patients with acute myeloid leukemia (AML) but not in hematopoietic stem and progenitor cells derived from normal individuals. Stable knockdown of CDX2 expression by RNA interference inhibited the proliferation of various human AML cell lines and strongly reduced their clonogenic potential in vitro. Primary murine hematopoietic progenitor cells transduced with Cdx2 acquired serial replating activity, were able to be continuously propagated in liquid culture, generated fully penetrant and transplantable AML in BM transplant recipients, and displayed dysregulated expression of Hox family members in vitro and in vivo. These results demonstrate that aberrant expression of the developmental regulatory gene CDX2 in the adult hematopoietic compartment is a frequent event in the pathogenesis of AML; suggest a role for CDX2 as part of a common effector pathway that promotes the proliferative capacity and self-renewal potential of myeloid progenitor cells; and support the hypothesis that CDX2 is responsible, in part, for the altered HOX gene expression that is observed in most cases of AML.