title: 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.
abstract: 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.
authors.affiliation: Department of Medicine III, Klinikum Grosshadern, Germany.
authors.forename: Vijay P S
authors.initials: VP
authors.lastname: Rawat
authors.forename: Silvia
authors.initials: S
authors.lastname: Thoene
authors.forename: Vegi M
authors.initials: VM
authors.lastname: Naidu
authors.forename: Natalia
authors.initials: N
authors.lastname: Arseni
authors.forename: Bernhard
authors.initials: B
authors.lastname: Heilmeier
authors.forename: Klaus
authors.initials: K
authors.lastname: Metzeler
authors.forename: Konstantin
authors.initials: K
authors.lastname: Petropoulos
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Deshpande
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Michaela
authors.initials: M
authors.lastname: Feuring-Buske
authors.forename: Christian
authors.initials: C
authors.lastname: Buske
mesh_terms: D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D016026:Bone Marrow Transplantation; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors