Rawat Vijay P S, Thoene Silvia, Naidu Vegi M, Arseni Natalia, Heilmeier Bernhard, Metzeler Klaus, Petropoulos Konstantin, Deshpande Aniruddha, Quintanilla-Martinez Leticia, Bohlander Stefan K, Spiekermann Karsten, Hiddemann Wolfgang, Feuring-Buske Michaela, Buske Christian
Department of Medicine III, Klinikum Grosshadern, Germany.
Blood. 2008 Jan 1;111(1):309-19. doi: 10.1182/blood-2007-04-085407. Epub 2007 Sep 12.
The mechanisms underlying deregulation of HOX gene expression in AML are poorly understood. The ParaHox gene CDX2 was shown to act as positive upstream regulator of several HOX genes. In this study, constitutive expression of Cdx2 caused perturbation of leukemogenic Hox genes such as Hoxa10 and Hoxb8 in murine hematopoietic progenitors. Deletion of the N-terminal domain of Cdx2 abrogated its ability to perturb Hox gene expression and to cause acute myeloid leukemia (AML) in mice. In contrast inactivation of the putative Pbx interacting site of Cdx2 did not change the leukemogenic potential of the gene. In an analysis of 115 patients with AML, expression levels of CDX2 were closely correlated with deregulated HOX gene expression. Patients with normal karyotype showed a 14-fold higher expression of CDX2 and deregulated HOX gene expression compared with patients with chromosomal translocations such as t(8:21) or t(15;17). All patients with AML with normal karyotype tested were negative for CDX1 and CDX4 expression. These data link the leukemogenic potential of Cdx2 to its ability to dysregulate Hox genes. They furthermore correlate the level of CDX2 expression with HOX gene expression in human AML and support a potential role of CDX2 in the development of human AML with aberrant Hox gene expression.
急性髓系白血病（AML）中HOX基因表达失调的潜在机制目前尚不清楚。已证明副同源盒基因CDX2可作为多种HOX基因的正向上游调节因子。在本研究中，Cdx2的组成型表达导致小鼠造血祖细胞中白血病相关的Hox基因（如Hoxa10和Hoxb8）出现紊乱。删除Cdx2的N末端结构域消除了其干扰Hox基因表达以及在小鼠中引发急性髓系白血病（AML）的能力。相比之下，Cdx2假定的Pbx相互作用位点失活并未改变该基因的白血病致癌潜力。在对115例AML患者的分析中，CDX2的表达水平与HOX基因表达失调密切相关。与具有染色体易位（如t(8;21)或t(15;17)）的患者相比，核型正常的患者CDX2表达及HOX基因表达失调水平高14倍。所有检测的核型正常的AML患者CDX1和CDX4表达均为阴性。这些数据将Cdx2的白血病致癌潜力与其失调Hox基因的能力联系起来。它们还将CDX2的表达水平与人类AML中的HOX基因表达相关联，并支持CDX2在具有异常Hox基因表达的人类AML发生中可能发挥的作用。
