Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model
Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model
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DOI：
10.1073/pnas.0604579103
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发表时间：
2006-11-07
影响因子：
11.1
通讯作者：
Huntly, Brian J. P.
中科院分区：
文献类型：
--
作者：
Bansal, Dimple;Scholl, Claudia;Huntly, Brian J. P.
HOX 基因已成为白血病发生的关键效应子，但调节其在白血病中表达的机制尚不清楚。最近的数据表明，尾部同源框转录因子 CDX1、CDX2 和 CDX4（HOX 基因表达的发育调节因子）可能导致白血病中 HOX 基因失调。我们在此报告，CDX4 在早期造血祖细胞中正常表达，并在大约 25% 的急性髓系白血病 (AML) 患者样本中异常表达。 Cdx4 调节成年小鼠造血系统中的 Hox 基因表达，并使与白血病发生有关的 Hox 基因失调。此外，经过逆转录病毒工程改造表达Cdx4的骨髓祖细胞在甲基纤维素培养物中连续重新铺板，在液体培养物中生长，并在骨髓移植受者中产生部分渗透性、长潜伏期的AML。 Hox 辅因子 Meis1a 的共表达可加速 Cdx4 AML 表型并使其完全渗透。结构功能分析表明，白血病转化需要完整的 Cdx4 反式激活和 DNA 结合结构域，但不需要假定的 Pbx 辅因子相互作用基序。总之，这些数据表明，Cdx4 在成人造血过程中调节 Hox 基因表达，并可能在诱导急性白血病中充当 Hox 基因表达的上游调节因子。由于许多人类白血病表现出一系列 HOX 家族成员的表达失调，这些集体发现也表明 CDX4 表达在急性白血病的发生中发挥着核心作用。
HOX genes have emerged as critical effectors of leukelmogenesis, but the mechanisms that regulate their expression in leukemia are not well understood. Recent data suggest that the caudal homeobox transcription factors CDX1, CDX2, and CDX4, developmental regulators of HOX gene expression, may contribute to HOX gene dysregulation in leukemia. We report here that CDX4 is expressed normally in early hernatopoietic progenitors and is expressed aberrantly in approximate to 25% of acute myeloid leukemia (AML) patient samples. Cdx4 regulates Hox gene expression in the adult murine hernatopoietic system and dysregulates Hox genes that are implicated in leukemogenesis. Furthermore, bone marrow progenitors that are retrovirally engineered to express Cdx4 serially replate in methylcellulose cultures, grow in liquid culture, and generate a partially penetrant, long-latency AML in bone marrow transplant recipients. Coexpression of the Hox cofactor Meis1a accelerates the Cdx4 AML phenotype and renders it fully penetrant. Structure-function analysis demonstrates that leukemic transformation requires intact Cdx4 transactivation and DNA-binding domains but not the putative Pbx cofactor interaction motif. Together, these data indicate that Cdx4 regulates Hox gene expression in adult hematopoiesis and may serve as an upstream regulator of Hox gene expression in the induction of acute leukemia. Inasmuch as many human leukemias show dysregulated expression of a spectrum of HOX family members, these collective findings also suggest a central role for CDX4 expression in the genesis of acute leukemia.