The role of Hox proteins in leukemogenesis: insights into key regulatory events in hematopoiesis.
The role of Hox proteins in leukemogenesis: insights into key regulatory events in hematopoiesis.
复制标题
HOX蛋白在白血病发生中的作用：对造血中关键调节事件的见解。
DOI：
10.1615/critrevoncog.v16.i1-2.70
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发表时间：
2011
影响因子：
--
通讯作者：
Eklund E
中科院分区：
文献类型：
--
作者：
Eklund E
急性髓系白血病（AML）是一种异质性疾病，预后高度可变。复发性染色体易位的识别为个体AML受试者提供了一些预后信息。基于人群的基因表达谱研究也发现了与预后相关的异常。这些研究将一组同源域转录因子的表达增加与AML的不良预后相关联。该集合包括HoxB 3、B4、A7-11和Meis 1，它们在预后不良的AML中作为一组在骨髓中失调。这些同源结构域转录因子的异常表达见于伴有涉及MLL、MYST 3和CREBBP基因的染色体易位的AML和具有正常细胞遗传学的预后不良亚组。在小鼠模型中的研究表明，Hox蛋白过表达对于髓系恶性肿瘤具有功能意义。单个Hox蛋白的过表达在体外扩增了各种骨髓群体，导致骨髓增殖，并且在某些情况下在体内导致分化阻滞和AML。因此，关键Hox靶基因的表达失调可能导致AML的不良预后。这些基因的鉴定将提供对AML预后的病理生物学的见解。研究开始确定Hox靶基因，这可能是治疗这种预后不良的白血病亚群的合理靶点。
Acute myeloid leukemia (AML) is a heterogeneous disease with highly variable prognosis. Identification of recurring chromosomal translocations provides some prognostic information for individual AML subjects. Population based gene expression profiling studies also identified abnormalities relevant to prognosis. Such studies associate increased expression of a set of homeodomain transcription factors with poor prognosis in AML. This set includes HoxB3, B4, A7–11 and Meis1, which are dysregulated as a group in the bone marrow in poor prognosis AML. Aberrant expression of these homeodomain transcription factors is found in AML with chromosomal translocations involving the MLL, MYST3 and CREBBP genes, and in a poor prognosis subset with normal cytogenetics. Studies in murine models suggest that Hox protein overexpression is functionally significant for myeloid malignancies. Overexpression of individual Hox proteins expanded various bone marrow populations in vitro, leading to myeloproliferation and in some cases differentiation block and AML in vivo. Therefore, dysregulated expression of key Hox target genes may contribute to adverse prognosis in AML. Identification of these genes will provide insights into the pathobiology of prognosis in AML. Studies are beginning to identify Hox target genes which may be rational targets for therapeutic approaches to this poor prognosis leukemia subset.