Myc/p27 balance in chronic lymphocytic leukemia

Trabajo presentado al "22th Biennial Congress of the European Association for Cancer Research" celebrado en Barcelona del 7 al 10 de julio de 2012.-- et al.
[Background]: Chronic Iymphocytic leukemia (CLL) is the most common leukemia in the western world. CLL is characterized by the accumulation of CD5+ 8 Iymphocytes. However, clinical outcome of CLL may be different. Some patients have an indolent leukemia with long survival while others experience an aggressive disease. Contrary to other human malignancies, the cyclin-dependent kinase inhibitor p27kip1 (p27) has been described to be overexpressed in CLL cells. On the other hand, Myc is an oncogenic transcription factor overexpressed in many human tumours. In recent years, work in several cellular models have demonstrated that Myc, through different mechanisms, antagonize p27 express ion and its anti-proliferatice activity. Thus we set out to study the interaction functional between p27 and Myc in 8-CLL and whether changes in p27/Myc ratio correlated with the clinic features of the disease. [Material and Methods]: Protein and mRNA levels of Myc and p27 in CLL patients and Mec1 cells were analyzed by Western 810t and real time RTPCR. We studied p27 and Myc localization by immunofluorescence. Annexin assay was performed to study the fludarabine resistance. SPSS and GraphPad Prism were used for statistical studies. [Results]: We studied expression levels of p27 and Myc in more than 100 CLL patients using peripheral blood, tonsil and CD19+ Iymphocytes as control. p27 and Myc levels were inversely correlated. Thus, the ratio between p27 (overexpressed) and Myc (downregulated) appears inverted in CLL with respect to the other tumours so far known. Moreover, low p27 and high Myc express ion correlated with the expression of Skp2, a subunit of ubiquitin protein ligase complex SCF which is the main responsible for p27 degradation. Skp2 is a Myc target gene and promotes the degradation of p27, suggesting a pathway Myo-Skp2-p27 in CLL. To investigate why p27 is expressed in CLL we overexpressed in a CLL-derived cellline (Mec1) and observed that high levels of p27 provide resistance to fludarabine treatment. In fact, p27 expression was strongly correlated with Bcl2 levels, an antiapoptotic protein, in CLL samples. [Conclusions]: Our data provide new insights into the p27/Myc balance in CLL cells. The high percentage of p27 overexpressed patients suggests an important function in CLL. causing low levels of Myc and increasing resistan ce to apoptosis, likely through collaboration with 8c12. These resu lts suggest a functional explanation so as why p27 is overexpressed in CLL.