Age-specific differences in oncogenic pathway dysregulation and anthracycline sensitivity in patients with acute myeloid leukemia.

Abstract

To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients. Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young <or= 45 years, n = 175; elderly >or= 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity. Elderly AML patients as expected had worse overall survival and event-free survival compared with younger patients. Analysis of oncogenic pathways revealed that older patients had higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation (all P < .0001). Older patients were also less sensitive to anthracycline compared with younger patients with AML (P < .0001). Hierarchical clustering revealed that younger AML patients in cluster 2 had clinically worse survival, with high RAS, Src, and TNF pathway activation and in turn were less sensitive to anthracycline compared with patients in cluster 1. However, among elderly patients with AML, those in cluster 1 also demonstrated high RAS, Src, and TNF pathway activation but this did not translate into differences in survival or anthracycline sensitivity. AML in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathway variations that contributes to poor survival and anthracycline resistance. These insights should enable development and adjustments of clinically meaningful treatment strategies in the older patient population.