Comprehensive HOX Gene Expression Profiles Are Associated with Major Cytogenetic Prognostic Categories in AML.

The homeodomain genes comprise a set of transcription factors that determine cell fate by regulating proliferation, development, and apoptosis. Humans have 39 class I homeodomain genes (HOX) that occur in four clusters (HOXA, HOXB, HOXC, and HOXD). During development HOX expression takes place according to the position of a gene within its cluster and the position of the cell along the anterior - posterior axis. Some HOX genes are expressed in adult tissues, where they are thought to regulate the regenerative differentiation of cells. If one were to view leukemia as a disorder of regenerative hematopoesis, one could hypothesize that dysregulation of HOX expression promotes leukemogenesis. The role of some homeodomain genes in acute leukemia has been especially well studied. In mouse model systems, overexpression of HOXA7, HOXA9 and Meis1 lead to AML. Chromosomal translocations targeting HOX and other homeodomain genes are associated with acute myeloid and lymphoid leukemias. Previous results have suggested that HOX expression patterns might define certain AML subsets. In the present study, we analyzed the expression of 40 homeodomain genes, among them 25 of the HOXA-D genes, in leukemic enriched samples from 66 patients with de novo AML and in sorted CD34+ cells derived from four healthy bone marrow donors. Also, in order to integrate any effects of mutations in FLT3, C/EBPa, and nucleophosmin (NPM) on HOX expression, we assessed the presence of mutations in these three genes. Our results demonstrate that HOX expression patterns are intimately linked to particular cytogenetic abnormalities. The most striking overall findings were the overexpression of HOXA and HOXB genes in AMLs with NPM mutations, the similarity of HOX expression in AMLs with unfavorable cytogenetics to that of AMLs with intermediate cytogenetics, and the downregulation of HOXA genes in core binding factor (CBF) AMLs. Moreover, AMLs with translocations involving CBFbeta had distinctly higher expression of HOXB2, HOXB3, HOXB4, and Meis 1 than did patients with translocations involving CBFalpha. Some HOX genes displayed no heterogeneity of expression and are thus likely unrelated to leukemogenesis. Other genes, particularly HOXA and HOXB genes, displayed marked heterogeneity of expression and thus may have a role in leukemogenesis. However, every AML had substantial differences in the expression of at least one HOX gene compared to normal CD34+ cells. In addition, levels of HOX expression distinguished within individual cytogenetic groups certain subsets, including cases with inv(16) and cases that phenotypically resembled NPM mutations. Based on these results and the causative nature of HOX deregulation in some acute leukemias, we postulate that the HOX expression patterns exemplified here may be responsible for some (or many) of the biologic differences observed among the major cytogenetic prognostic groups.