Acute myeloid leukemia (AML) is a heterogeneous group of diseases. Patients exhibiting normal cytogenetics (AML-CN) constitute the single largest group, and trisomy 8 (AML+8) as the sole abnormality is the most frequent trisomy. How trisomy contributes to tumorigenesis is unknown. Because hematopoietic differentiation is predominantly regulated at the transcriptional level, we proposed that, whatever the underlying molecular leukemogenic event(s) associated with AML-CN and AML+8, the molecular changes at the DNA level should be reflected in specific changes at the RNA level. We used oligonucleotide-based DNA microarrays to study global gene expression in ten AML+8 patients with +8 as the sole chromosomal abnormality and ten AML-CN patients, as well as seven CD34+ cell samples purified from normal bone marrow of healthy individuals as a representative heterogeneous population of stem and progenitor cells. For the 6,606 genes studied, expression patterns of AML patients were clearly distinct from those of CD34+ cells of normal individuals. AML+8 was associated with an overexpression of genes on chromosome 8, suggesting a role for gene dosage effects in the etiology of AML+8. Systematic analysis by cellular function indicated upregulation of genes involved in cell adhesion in both AML groups. We observed other highly significant results in the comparison of AML+8 with AML-CN for genes involved in the regulation of apoptosis, suggesting a fundamental biological difference in programmed cell death. The observed differences in the dysregulation of specific functional subsets of genes between the two AML subclasses merit further functional studies of the individual components of the pathways.