Distinct Gene Expression Profiling in AML in Elderly Versus Younger Patients

Acute myeloid leukaemia (AML) has a different clinical and biological behaviour in elderly patients. We used Affymetrix HGU133Plus2.0 gene expression data of 525 patients with AML -who were treated on various HOVON/SAKK studies-to ascertain the difference of gene expression profiles in AML samples of older patients compared to AML samples of younger patients. Differentially expressed genes were identified for 175 youngest with a median age of 31-years vs. 175 oldest AML patients with a median age of 59-years using a multivariate permutation test in Biometric Research Branch ArrayTools (BRB ArrayTools). This analysis revealed that 478 probes were up-regulated and 492 probes were down-regulated with increasing age at the significance level of P <1.0×10⁻⁵. Biological processes (represented by GO-categories) enriched among the 478 (up) and 492 (down) differentially expressed probes were identified. Processes as regulation of cell proliferation, negative regulation of apoptosis as well as response to stress were up regulated with increasing age, whereas processes as chromatin modification, programmed cell death as well as transcription repressor activity were found to be down regulated with increasing age. It was striking that the tumour suppressor gene p16^INK4a was identified as one of the strongest down-regulated genes with age. In contrast, various studies have demonstrated an increasing expression of p16^INK4a during physiological ageing. Downregulation of p16^INK4a with increasing age was confirmed in an independent cohort of CD34+ cells of 54 AML patients, whereas in CD34+ cells of 23 healthy volunteers p16^INK4a was found to be upregulated with increasing age. In conclusion, gene expression profiles of AML samples of young and old patients differ significantly. That these differences in gene expression profiles not simply reflect an ageing phenomenon is illustrated by the down regulation of p16^INK4a in samples of elderly AML patients. These data suggest that counteracting the senescence-promoting increase in p16^INK4a, which is associated with physiological ageing, plays an important role in the development of AML in elderly patients.