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
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Juan M. Caraballo1, Juan C. Acosta1, 8, Miguel A. Cortés2, Marta Albajar3, M. Teresa Gómez-Casares4, Ana Batlle-López3, M. Angeles Cuadrado3, Arantza Onaindia5, Gabriel Bretones1, Javier Llorca6, Miguel A. Piris5, Dolors Colomer7, Javier León1
1 Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-Sodercan, and Dpt. of. Biología Molecular, Universidad de Cantabria, Santander, Spain.
2 Hospital de Laredo, Laredo, Santander, Spain.
3 Servicio de Hematologia, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
4 Servicio de Hematología, Hospital Dr. Negrin, Las Palmas, Spain.
5 Servicio de Anatomía Patológica, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
6 Group of Epidemiology and Computational Biology, Universidad de Cantabria-IDIVAL, Santander, Spain and CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
7 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain.
8 Present address: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.
Dr. Javier León, e-mail: [email protected]
Keywords: p27, Myc, Skp2, fludarabine, chronic lymphocytic leukemia
Received: February 11, 2014 Accepted: June 09, 2014 Published: June 20, 2014
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.
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