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

IntroductionIn recent years, substantial progress has been made in understanding the biology of acute myeloid leukemia (AML). One of the pathogenetic hallmarks of AML are chromosomal translocations generating leukemogenic fusion genes that often act as aberrant transcription factors. 1 The second key genetic characteristics in AML are mutations, particularly those found in patients with normal karyotype and affecting the receptor tyrosine kinase FLT3 or the nucleophosmin protein (NPM1). Beside these structural genetic changes, large-scale gene expression analyses of cDNA samples from patients with AML have demonstrated that deregulated expression of nonaltered genes characterizes many AML cases. The most prominent example for this is the deregulated expression of homeobox genes in AML. [2][3][4] Homeobox genes form a highly conserved family of transcription factors known to be key regulators of normal hematopoietic stem cell and progenitor development. 5 Several studies have demonstrated that aberrant HOX gene expression profoundly perturbs normal murine and human hematopoietic development and causes leukemia in mice. [5][6][7][8][9] The aberrant expression of homeobox genes such as HOXA9 and HOXA10 is strongly associated with certain AML subtypes characterized by MLL fusion genes, NPM1 mutations (NPMc ϩ ), and by more rare translocations such as the translocation t(10;11)(p13q14) generating the CALM-AF10 fusion gene. 4,[10][11][12][13] All together, deregulated homeobox gene expression characterizes more than every third case of AML. So far, it is largely unknown how the aberrant expression of homeobox genes is initiated in the malignant clone. In cases with 11q23 chromosomal translocations, it is thought that aberrant function of the MLL gene, a known positive upstream regulator of HOX gene expression, is responsible for the perturbed expression of these key regulatory genes of early hematopoietic development. 14 In contrast, the aberrant HOX gene expression in patients with AML with normal karyotype and NPM1 mutation is not well understood. 15 In particular, the patients with NPMc ϩ AML demonstrate that aberrant HOX gene expression cannot be just explained by the stage of differentiation at which the leukemic clone is arrested: NPMc ϩ patients are CD34 Ϫ in more than 95% of patients, and represent therefore a cell stage in which HOX genes are normally silenced. 8,16 Another gene family critically involved in Hox gene regulation is the family of the so-called ParaHox genes, comprising the different "caudal-related homeobox genes" such as CDX1, CDX2, and CDX4, and the GSH2 homeobox gene. 17 Several experimental systems have demonstrated that loss of Cdx2 causes homeotic alterations and posterior shifts in Hox expression domains, 18 and that consensus-binding sites for the 3 Cdx homologs are present in the promoters of multiple Hox genes. [19][20][21][22] Expression of Cdx2 is tightly restricted to intestinal development in the adult. 23 Aberrant expression of CDX2 is associated with intestinal metaplasia, 24,25...

The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia

“…Thus, it extends our knowledge about the deregulation of this transcription factor that was reported earlier to be one of the most frequent ectopically expressed proto-oncogenes in AML, 8,11 and underlines that aberrant expression of this homeobox gene is not restricted to myeloid malignancies. This aberrant expression of CDX2 in human leukemias stands in clear contrast to highly related genes such as CDX4 or CDX1, which were not expressed in our series of AML patients or were detected only in a minor fraction of patients with AML.…”

“…This aberrant expression of CDX2 in human leukemias stands in clear contrast to highly related genes such as CDX4 or CDX1, which were not expressed in our series of AML patients or were detected only in a minor fraction of patients with AML. 11,16 Furthermore, analyses of CDX4 expression in our series of ALL samples did not show expression of this ParaHox gene (data not shown). The reason for this is unknown.…”

“…Besides Hox genes, 11 enforced expression of Cdx2 in normal murine progenitors significantly upregulated genes involved in lymphopoiesis, such as Lef1 (3.9-fold), Tcf3 (13.3-fold), Flt3 (4.2-fold) and Id3 (10.2-fold) (Figure 2). …”

“…10 It was shown that CDX2 is among the most frequent aberrantly expressed proto-oncogenes in AML, with up to 89% of AML cases with normal karyotype expressing CDX2. 8,11 In AML patients, high expression levels of CDX2 were closely associated with HOX gene deregulation. 11 However, it was shown that besides Hox genes Cdx2 regulates other stem cell regulatory genes, such as Scl, Gata1 and Runx1.…”

“…8,11 In AML patients, high expression levels of CDX2 were closely associated with HOX gene deregulation. 11 However, it was shown that besides Hox genes Cdx2 regulates other stem cell regulatory genes, such as Scl, Gata1 and Runx1. 12 Thus, aberrant expression of CDX2 might perturb the stem cell regulatory network at different levels.…”