TY - JOUR T1 - The p53 transcriptional pathway is preserved in ATMmutated and NOTCH1mutated chronic lymphocytic leukemias. JF - Oncotarget Y1 - 2014 A1 - Athanasakis, Emmanouil A1 - Melloni, Elisabetta A1 - Rigolin, Gian Matteo A1 - Agnoletto, Chiara A1 - Voltan, Rebecca A1 - Vozzi, Diego A1 - Piscianz, Elisa A1 - Segat, Ludovica A1 - dal Monego, Simeone A1 - Cuneo, Antonio A1 - Secchiero, Paola A1 - Zauli, Giorgio KW - Aged KW - Aged, 80 and over KW - Ataxia Telangiectasia Mutated Proteins KW - Base Sequence KW - Female KW - Genes, p53 KW - Humans KW - Leukemia, Lymphocytic, Chronic, B-Cell KW - Male KW - Models, Molecular KW - Molecular Sequence Data KW - Mutation KW - Receptor, Notch1 KW - Signal Transduction KW - Tumor Suppressor Protein p53 AB -

By using next generation sequencing, we have analyzed 108 B chronic lymphocytic leukemia (B-CLL) patients. Among genes involved in the TP53 pathway, we found frequent mutations in ATM (n=18), TP53 (n=10) and NOTCH1 (n=10) genes, rare mutations of NOTCH2 (n=2) and CDKN1A/p21 (n=1) and no mutations in BAX, MDM2, TNFRSF10A and TNFRSF10B genes. The in vitro treatment of primary B-CLL cells with the activator of p53 Nutlin-3 induced the transcription of p53 target genes, without significant differences between the B-CLL without mutations and those harboring either ATM or NOTCH1mutations. On the other hand, the subgroup of TP53mutated B-CLL exhibited a significantly lower induction of the p53 target genes in response to Nutlin-3 as compared to the other B-CLL samples. However, among the TP53mutated B-CLL, those showing mutations in the high hot spot region of the DNA binding domain [273-280 aa] maintained a significantly higher p53-dependent transcriptional activity as compared to the other TP53mutated B-CLL samples. Since the ability to elicit a p53-dependent transcriptional activity in vitro has a positive prognostic significance, our data suggest that ATMmutated, NOTCH1mutated and surprisingly, also a subset of TP53mutated B-CLL patients might benefit from therapeutic combinations including small molecule activator of the p53 pathway.

VL - 5 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25587027?dopt=Abstract ER -