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The p53 transcriptional pathway is preserved in ATMmutated and NOTCH1mutated chronic lymphocytic leukemias

2014; Impact Journals LLC; Volume: 5; Issue: 24 Linguagem: Inglês

10.18632/oncotarget.2211

1949-2553

Emmanouil Athanasakis, E. Melloni, Gian Matteo Rigolin, Chiara Agnoletto, Rebecca Voltan, Diego Vozzi, Elisa Piscianz, Ludovica Segat, Simeone Dal Monego, Antonio Cuneo, Paola Secchiero, Giorgio Zauli,

Immunodeficiency and Autoimmune Disorders

// Emmanouil Athanasakis 1* , Elisabetta Melloni 2* , Gian Matteo Rigolin 3 , Chiara Agnoletto 2 , Rebecca Voltan 2 , Diego Vozzi 1 , Elisa Piscianz 1 , Ludovica Segat 1 , Simeone Dal Monego 4 , Antonio Cuneo 3 , Paola Secchiero 2 and Giorgio Zauli 1 1 Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy 2 Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy 3 Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy 4 Cluster in Biomedicine, CBM S.c.r.l., Bioinformatic Services, Area Science Park, Trieste, Italy * These authors contributed equally to this work Correspondence: Giorgio Zauli, email: // Keywords : B-CLL, p53, ATM, NOTCH1, Nutlin-3 Received : June 16, 2014 Accepted : July 11, 2014 Published : July 13, 2014 Abstract 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 NOTCH1 mutations. On the other hand, the subgroup of TP53 mutated 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 TP53 mutated 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 TP53 mutated B-CLL samples. Since the ability to elicit a p53-dependent transcriptional activity in vitro has a positive prognostic significance, our data suggest that ATM mutated , NOTCH1 mutated and surprisingly, also a subset of TP53 mutated B-CLL patients might benefit from therapeutic combinations including small molecule activator of the p53 pathway.