Nutlin-3 differentially modulates miRNA34a and miRNA181 versus miR26a and miR155 in p53 proficient and p53 deficient B chronic lymphocytic leukemia (B-CLL) samples

Excerpt

Despite impressive improvements in response rates of chronic lymphocytic leukemia (CLL) patients using the combination of fludarabine, cyclophosphamide and rituximab, patients refractory to this combination or patients that have suffered multiple disease relapses have a poor outcome [1, 2]. In cells with functional p53, the p53 activity is primarily inhibited through direct and tonic interaction with the human homolog of the murine double minute 2 (MDM2) protein. The small molecule Nutlin-3 was originally described as a potent and selective inhibitor of the p53/MDM2 interaction [3], able to rise the levels of p53 protein and to induce cell cycle arrest and/or apoptosis in a variety of tumor cell lines [3] including hematological malignancies [4]. The p53 gene is deleted (17p-) and/or mutated in <15% of B-CLL patients at diagnosis and in >30% of B-CLL patients with pre-treated disease [5]. 17p- as well as monoallelic mutation of TP53 in the absence or presence of 17p- deletion has been associated with a poor prognosis [5]. …