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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...

Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor of Wnt signaling. We recently showed that aberrant LEF1 expression induces acute myeloid leukemia (AML) in mice, and found high LEF1 expression in a subset of cytogenetically normal AML (CN-AML) patients. Whether LEF1 expression associates with clinical and molecular patient characteristics and treatment outcomes remained unknown. We therefore studied LEF1 expression in 210 adults with CN-AML treated on German AML Cooperative Group trials using microarrays. High LEF1 expression (LEF1 high ) associated with significantly better relapse-free survival (RFS; P < .001), overall survival (OS; P < .001), and event-free survival (EFS; P < .001). In multivariable analyses adjusting for established prognosticators, LEF1 high status remained associated with prolonged RFS (P ‫؍‬ .007), OS (P ‫؍‬ .01), and EFS (P ‫؍‬ .003). In an independent validation cohort of 196 CN-AML patients provided by the German-Austrian AML Study Group, LEF1 high patients had significantly longer OS (P ‫؍‬ .02) and EFS (P ‫؍‬ .04). We validated the prognostic relevance of LEF1 expression by quantitative PCR, thereby providing a clinically applicable platform to incorporate this marker into future risk-stratification systems for CN-AML. Gene-expression profiling and immunophenotyping revealed upregulation of lymphopoiesis-related genes and lymphoid cell-surface antigens in LEF1 high patients. In summary, we provide evidence that high LEF1 expression is a novel favorable prognostic marker in

Recent data indicate that a variety of regulatory molecules active in embryonic development may also play a role in the regulation of early hematopoiesis. Here we report that the human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus xvent2 gene, is a unique regulatory hematopoietic gene that is aberrantly expressed in CD34 + leukemic stem-cell candidates in human acute myeloid leukemia (AML). Quantitative RT-PCR documented expression of the gene in lineage positive hematopoietic subpopulations, with the highest expression in CD33 + myeloid cells. Notably, expression levels of VENTX were negligible in normal CD34 + /CD38 − or CD34 + human progenitor cells. In contrast to this, leukemic CD34 + / CD38 − cells from AML patients with translocation t(8,21) and normal karyotype displayed aberrantly high expression of VENTX. Gene expression and pathway analysis demonstrated that in normal CD34 + cells enforced expression of VENTX initiates genes associated with myeloid development and down-regulates genes involved in early lymphoid development. Functional analyses confirmed that aberrant expression of VENTX in normal CD34 + human progenitor cells perturbs normal hematopoietic development, promoting generation of myeloid cells and impairing generation of lymphoid cells in vitro and in vivo. Stable knockdown of VENTX expression inhibited the proliferation of human AML cell lines. Taken together, these data extend our insights into the function of embryonic mesodermal factors in human postnatal hematopoiesis and indicate a role for VENTX in normal and malignant myelopoiesis.human | myelopoiesis | Xvent | VENTX2

Molecular characterization of acute lymphoblastic leukemia (ALL) has greatly improved the ability to categorize and prognostify patients with this disease. In this study, we show that the proto-oncogene CDX2 is aberrantly expressed in the majority of cases with B-lineage ALL and T-ALL. High expression of CDX2 correlated significantly with the ALL subtype pro-B ALL, cALL, Ph þ ALL and early T-ALL. Furthermore, high expression of CDX2 was associated with inferior overall survival and showed up as a novel and strong risk factor for ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in adult patients with ALL.