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

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

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)12635-12645
Number of pages11
JournalOncotarget
Volume5
Issue number24
Publication statusPublished - 2014

    Fingerprint

Keywords

  • ATM
  • B-CLL
  • NOTCH1
  • Nutlin-3
  • P53

ASJC Scopus subject areas

  • Oncology

Cite this

Athanasakis, E., Melloni, E., Rigolin, G. M., Agnoletto, C., Voltan, R., Vozzi, D., Piscianz, E., Segat, L., Dal Monego, S., Cuneo, A., Secchiero, P., & Zauli, G. (2014). The p53 transcriptional pathway is preserved in ATMmutated and NOTCH1mutated chronic lymphocytic leukemias. Oncotarget, 5(24), 12635-12645.