The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Abstract

Introduction: The prognosis of chronic myeloid leukemia (CML) patients has been dramatically improved with the introduction of imatinib (IM), the first tyrosine kinase inhibitor (TKI). TKI resistance is a serious problem in IM-based therapy. The human S-phase kinase-associated protein 2 (SKP2) gene may play an essential role in the genesis and progression of CML. Aim of the study: We try to explore the diagnostic/prognostic impact of SKP2 gene expression to predict treatment response in first-line IM-treated CML patients at an early response stage. Patients and methods: The gene expression and protein levels of SKP2 were determined using quantitative RT-PCR and ELISA in 100 newly diagnosed CML patients and 100 healthy subjects. Results: SKP2 gene expression and SKP2 protein levels were significantly upregulated in CML patients compared to the control group. The receiver operating characteristic (ROC) analysis for the SKP2 gene expression level, which that differentiated the CML patients from the healthy subjects, yielded a sensitivity of 86.0% and a specificity of 82.0%, with an area under the curve (AUC) of 0.958 (p < 0.001). The ROC analysis for the SKP2 gene expression level, which differentiated optimally from the warning/failure responses, yielded a sensitivity of 70.59% and a specificity of 71.21%, with an AUC of 0.815 (p < 0.001). Conclusion: The SKP2 gene could be an additional diagnostic and an independent prognostic marker for predicting treatment responses in first-line IM-treated CML patients at an early time point (3 months).

Keywords: SKP2 gene expression; chronic myeloid leukemia; imatinib; treatment response.

Figure 1

The relative mRNA expression levels of SKP2 at the time of diagnosis (n = 100), at 3 months after IM in CML patients (n = 100) and the control subjects (n = 100). The blue symbols represent the relative mRNA expression levels of SKP2 gene at the time of diagnosis; the pink symbols represent the relative mRNA expression levels of SKP2 gene 3 months after IM; and the green symbols represent the relative mRNA expression levels of SKP2 gene of the control subjects. p₁: p value for Wilcoxon signed-ranks test for comparison between the relative mRNA expression levels of SKP2 gene of CML patients at the time of diagnosis and 3 months after IM. p₂: p value for Mann–Whitney test for comparison between the relative mRNA expression levels of SKP2 gene at the time of diagnosis and the control subjects. p₃: p value for Mann–Whitney test for comparison between the relative mRNA expression levels of SKP2 gene 3 months after IM and the control subjects. *: statistically significant at p ≤ 0.05.

Figure 2

SKP2 protein levels (ELISA) at the time of diagnosis, at 3 months after IM in CML patients (n = 100) and the control subjects (n = 100). The blue symbols represent the SKP2 protein levels at the time of diagnosis; the pink symbols represent SKP2 protein levels 3 months after IM; and the green symbols represent SKP2 protein levels of the control subjects. p₁: p value for Wilcoxon signed-ranks test for comparison between the SKP2 protein levels of CML patients at the time of diagnosis and 3 months after IM. p₂: p value for Mann–Whitney test for comparison between the SKP2 protein levels at the time of diagnosis and the control subjects. p₃: p value for Mann–Whitney test for comparison between the SKP2 protein levels 3 months after IM and the control subjects. *: statistically significant at p ≤ 0.05.

Figure 3

ROC curve for relative expression of SKP2 to discriminate CML patients (n = 100) from the control subjects (n = 100).

Figure 4

ROC curve for relative expression of SKP2 at the time of diagnosis to predict treatment response (discriminate optimal response from warning/failure response).