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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model
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Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model

机译：Cdx4异常调节Hox基因表达并单独和在小鼠模型中与Meis1a协同产生急性髓细胞性白血病

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摘要

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.
机译：HOX基因已成为白血病发生的关键效应器，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，尾同源异形盒转录因子CDX1，CDX2和CDX4是HOX基因表达的发育调节因子，可能是白血病中HOX基因失调的原因。我们在这里报告CDX4在早期的造血祖细胞中正常表达，并在大约25％的急性髓细胞性白血病（AML）患者样本中异常表达。 Cdx4调节成年小鼠造血系统中Hox基因的表达，并失调与白血病发生有关的Hox基因。此外，经逆转录病毒工程改造以表达Cdx4的骨髓祖细胞在甲基纤维素培养物中连续重铺，在液体培养物中生长，并在骨髓移植受体中产生部分渗透的长潜伏期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结合域，而不需要假定的Pbx辅因子相互作用基序。总之，这些数据表明Cdx4调节成人造血中的Hox基因表达，并且可以在诱导急性白血病中充当Hox基因表达的上游调节剂。由于许多人类白血病显示HOX家族成员谱的表达失调，这些共同的发现也表明CDX4表达在急性白血病的发生中起着核心作用。

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