Gene Expression Profiling Differentiates Childhood Acute Lymphoblastic Leukemia in Down Syndrome Versus Non-Down Syndrome Patients.

Abstract

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) form a unique biological subset. These patients have generally inferior outcomes in many studies, and an increased incidence of treatment-related toxicities. Cases of DS ALL have a much lower frequency of recurrent prognostically significant chromosomal abnormalities than cases of ALL in the general pediatric population. Global gene expression profiling provides an opportunity to gain insights into pathogenesis and potential therapeutic targets in DS ALL. We performed microarray analysis of RNA from bone marrow samples obtained at diagnosis in 30 DS ALL and 24 non-DS ALL cases using the Affymetrix Human Genome U133 Plus 2.0 array. Unsupervised hierarchical clustering separated cases into two main groups, one of which included 21 of 30 DS samples (Fisher's exact test, p = 0.013), suggesting inherent biologic similarities. Non-DS samples clustered according to known cytogenetic features. Consistent with recently published data, a subset (13%) of our DS ALL cases were found to have JAK2 mutations. Cases of DS ALL bearing JAK2 mutations did not form a distinct subcluster, suggesting that the JAK2 pathway may be dysregulated via other events in cases of DS ALL with wild-type JAK2. Two-sample comparison of DS versus non-DS ALL cases demonstrated differential expression of 513 genes with p values <0.001 (Figure 1). Oxidative phosphorylation pathway genes were most over-represented among differentially expressed genes, with 35 of 115 genes in this pathway demonstrating down-regulation in DS compared to non-DS ALL (Bonferroni corrected p value < 1 ×10−9), including several cytochrome c oxidase and ubiquinone subunits. Our data indicate that DS ALL blasts may utilize oxidative phosphorylation to a lesser extent than non-DS ALL, a feature which could be exploited therapeutically.The top 513 genes differentially expressed in DS versus non-DS ALL (Benjamini-Hochberg corrected p values < 0.001) are displayed in a heatmap where genes relatively overexpressed in DS ALL are depicted in yellow, and relatively underexpressed in DS ALL in red. DS ALL cases are indicated by red circles and non-DS ALL cases by white circles. Four DS ALL cases bearing a JAK2 mutation at arginine 683 are indicated by black stars. [Display omitted]