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 Blood, 1 January 2008, Vol. 111, No. 1, pp. 309-319.
Prepublished online as a Blood First Edition Paper on September 12, 2007; DOI 10.1182/blood-2007-04-085407.

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NEOPLASIA

Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia

Vijay P. S. Rawat1,2, Silvia Thoene1,2, Vegi M. Naidu1,2, Natalia Arseni1,2, Bernhard Heilmeier1, Klaus Metzeler1, Konstantin Petropoulos1,2, Aniruddha Deshpande1,2, Leticia Quintanilla-Martinez3, Stefan K. Bohlander1,2, Karsten Spiekermann1,2, Wolfgang Hiddemann1,2, Michaela Feuring-Buske1,2, and Christian Buske1,2

1 Department of Medicine III, Klinikum Grosshadern and 2 Clinical Cooperative Group (CCG) Leukemia, National Research Center for Environment and Health (GSF), Munich; and 3 Institute of Pathology, GSF, Neuherberg, Germany

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.


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