The p53 transcriptional pathway is preserved in ATMmutated and NOTCH1mutated chronic lymphocytic leukemias
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Emmanouil Athanasakis1*, Elisabetta Melloni2*, Gian Matteo Rigolin3, Chiara Agnoletto2, Rebecca Voltan2, Diego Vozzi1, Elisa Piscianz1, Ludovica Segat1, Simeone Dal Monego4, Antonio Cuneo3, Paola Secchiero2 and Giorgio Zauli1
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
Giorgio Zauli, email:
Keywords: B-CLL, p53, ATM, NOTCH1, Nutlin-3
Received: June 16, 2014 Accepted: July 11, 2014 Published: July 13, 2014
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.
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