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HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias

机译:HOX介导的胚胎中胚层LmO2表达在急性白血病中得到了重演

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摘要

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.Oncogene advance online publication, 27 May 2013; doi:10.1038/onc.2013.175.
机译:Lim Domain Only 2(LMO2)白血病致癌基因编码早期造血所需的LIM域转录辅因子。在胚胎发生过程中,LMO2也表达在发育中的尾巴和四肢芽中,我们现在显示出这种表达模式已通过LMO2内含子4的增强子在转基因小鼠中得以概括。肢芽的表达取决于HOX结合位点簇,而后尾表达需要HOX网站和两个E-box。鉴于LMO2和HOX基因在急性白血病中的重要性,我们进一步证明了LMO2的HOX调控的调控机制在白血病小鼠模型以及患者样品中均得到激活。此外,Lmo2敲低损害了白血病细胞的生长,诊断时LMO2的高表达与细胞遗传学正常AML患者的不良生存相关。综上所述,这些结果建立了正常发育过程中对LMO2的HOX控制的调节等级,可以在白血病发生过程中复活。除了异位激活LMO2的特定实例外,在异常情况下重新部署胚胎监管体系可能与人类病理学相关。《致癌基因》在线提前发表,2013年5月27日; doi:10.1038 / onc.2013.175。

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