Abstract
MicroRNAs (miRNAs) are post-transcriptional regulators that regulate gene expression by binding to the 3′ untranslated region of target mRNAs. Mature miRNAs transcribed from the miR-17-92 cluster have an oncogenic activity, which are overexpressed in chronic-phase chronic myelogenous leukemia (CML) patients compared with normal individuals. Besides, the tyrosine kinase activity of BCR-ABL oncoprotein from the Philadelphia chromosome in CML can affect this miRNA cluster. Genes with similar mRNA expression profiles are likely to be regulated by the same regulators. We hypothesize that target genes regulated by the same miRNA are co-expressed. In this study, we aim to explore the difference in the co-expression patterns of those genes potentially regulated by miR-17-92 cluster between the normal and the CML groups. We applied a statistical method for gene pair classification by identifying a disease-specific cutoff point that classified the co-expressed gene pairs into strong and weak co-expression classes. The method effectively identified the differences in the co-expression patterns from the overall structure. Functional annotation for co-expressed gene pairs showed that genes involved in the metabolism processes were more likely to be co-expressed in the normal group compared to the CML group. Our method can identify the co-expression pattern difference from the overall structure between two different distributions using the distribution-based statistical method. Functional annotation further provides the biological support. The co-expression pattern in the normal group is regarded as the inter-gene linkages, which represents the healthy pathological balance. Dysregulation of metabolism may be related to CML pathology. Our findings will provide useful information for investigating the novel CML mechanism and treatment.
Highlights
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cells (Salesse and Verfaillie, 2002)
Two-sample KS test was used to identify the difference from the overall structure. We found that these two distributions in the normal and CML groups were significantly different with p < 0.05 for the maximum deviation D = 0.0567 > Dcritical = 0.009 (Figure 1)
We can infer that these two co-expression patterns were so distinct that the normal group had more strongly co-expressed and less weakly co-expressed gene pairs compared to the CML group
Summary
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cells (Salesse and Verfaillie, 2002). Co-expression of miR-17-92 Target Genes (Melo and Barnes, 2007). Such fusion can increase the tyrosine kinase activity of ABL and the autophosphorylation of BCRABL oncoprotein, creating more binding sites for the interacting proteins (Melo and Barnes, 2007). More microarray studies have been performed in CML, such as the gene differential and co-expression analysis. The co-expression analysis is very powerful for grouping genes and further analyzing the underlying mechanisms of diseases. Gene co-expression patterns vary among different states and cell types (Torkamani et al, 2010). It was reported that genes with similar mRNA expression profiles tend to be regulated by the same mechanism(s), e.g., sharing common regulator (Altman and Raychaudhuri, 2001; Schulze and Downward, 2001)
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