High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.

Juan M Caraballo,Dolors Colomer,Marta Albajar,Javier Llorca,Miguel A Piris,M Teresa Gómez-Casares,Ana Batlle-López,Gabriel Bretones,Juan C Acosta,Arantza Onaindia,Miguel A Cortés,Javier León,M Angeles Cuadrado

doi:10.18632/oncotarget.2100

Abstract

Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2.

Highlights

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western countries and it is characterized by the progressive accumulation of clonalB lymphocytes in peripheral blood bone marrow and lymph nodes [1,2,3]
We found that low p27 and high Myc expression correlated with Skp2 suggesting a mechanistic explanation for Myc and p27 inverse correlation in chronic lymphocytic leukemia (CLL)
The results revealed an increase (~5 fold as a mean) in p27 mRNA in CLL samples, as compared to controls (Figure 1A) The analysis of the mRNA data loaded in the Oncomine databank revealed a high heterogeneity among different studies

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western countries and it is characterized by the progressive accumulation of clonalB lymphocytes in peripheral blood bone marrow and lymph nodes [1,2,3]. Patients with no mutation in the variable region of the immunoglobulin genes (IGH) or with high expression of CD38 or ZAP70 had an aggressive course, whereas patients with mutated IGH clones or low expression of CD38 or ZAP70 cells usually show an indolent course [1, 3] It has been reported alterations of cell cycle regulatory molecules in CLL, such as cyclin E, cyclin D, cyclin-dependent kinase (Cdk) 4 and Cdk2 [4, 5]. The Cdk inhibitor p27KIP1 (p27), that negatively controls cell-cycle progression, has been observed overexpressed in CLL cells [6,7,8] This is in contrast to the majority of human tumors, where low levels of p27 are found [9,10,11]. This is mostly carried out by the SCFSkp ubiquitin ligase complex, where Skp acts as the p27-recogninzing subunit [12,13,14]

Methods

Results

Conclusion