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Elevated S-Phase Kinase-Associated Protein 2 Protein Expression in Acute Myelogenous Leukemia

Its Association with Constitutive Phosphorylation of Phosphatase and Tensin Homologue Protein and Poor Prognosis

¹ Department of Internal Medicine, Yonsei University College of Medicine, Seoul; ² Brain Korea 21 Project for Medical Science, and ³ Clinical Research Center, Yonsei University College of Medicine, Seoul; and ⁴ Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea

Purpose: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G₁-S phase transition by controlling the stability of several G₁ regulators, such as p27Kip1. However, the clinical significance of Skp2 in patients with acute myelogenous leukemia (AML) remains unknown.

Experimental Design: We examined the clinical and biological significance of Skp2 expression in AML and evaluated the relationship between Skp2 and p27Kip1 expression and phosphatase and tensin homologue (PTEN) phosphorylation.

Results: Western blot analysis showed that high Skp2 expression was observed in 57 (57.6%) cases and significantly correlated with unfavorable cytogenetics (P = 0.035) but not with age, white blood cell count, serum lactic dehydrogenase level, and the French-American-British subtype. An inverse correlation was not observed between Skp2 and p27Kip1 expression. However, p27Kip1 protein was preferentially localized to cytoplasm in the high-Skp2-expression group. The cytoplasmic to nuclear ratio of p27Kip1 expression was significantly correlated with the levels of Skp2 expression (P < 0.001). The frequency of PTEN phosphorylation was significantly higher in the high-Skp2-expression group compared with the low- Skp2-expression group (P = 0.035). The Skp2 overexpression was significantly associated with shorter disease-free survival and overall survival (P = 0.0386 and P = 0.0369, respectively). Multivariate analysis showed that Skp2 expression was an independent prognostic factor both in the disease-free survival and overall survival.

Conclusion: These findings suggest that Skp2 expression is an independent marker for a poor prognosis in AML. The presence of a positive correlation between Skp2 and phosphorylated PTEN suggests that an aberration in the PTEN/Skp2 signaling pathway might be operating in AML.

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