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 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.
Highlights
IntroductionMutational status of the tumor protein p53 (TP53) gene has been one of the most important prognostic molecular markers in B-chronic lymphocytic leukemia (B-CLL) for a long time [1,2,3,4,5,6,7], more recently additional promising novel candidate genes have been described in B-CLL patients as results of wholeexome and/or whole-genome sequencing [8,9,10,11,12,13,14,15,16,17,18]
A recent study published by Rossi et al demonstrated that ultra-deepNGS significantly improved the detection of tumor protein p53 (TP53) genetic defects in B-chronic lymphocytic leukemia (B-CLL) allowing the identification of small TP53 mutated subclones among patients that would be otherwise considered wild type for the TP53 gene according to Sanger sequencing [27]
We documented that the presence of TP53 mutations predicted impairment of the transcriptional activation of TP53 target genes, as assessed by in vitro treatment with Nutlin-3
Summary
Mutational status of the tumor protein p53 (TP53) gene has been one of the most important prognostic molecular markers in B-chronic lymphocytic leukemia (B-CLL) for a long time [1,2,3,4,5,6,7], more recently additional promising novel candidate genes have been described in B-CLL patients as results of wholeexome and/or whole-genome sequencing [8,9,10,11,12,13,14,15,16,17,18]. Mutations in NOTCH1 have been described in 8-12% of newly diagnosed B-CLL patients with increasing frequencies www.impactjournals.com/oncotarget
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