Prognostic impact and landscape of NOTCH1 mutations in chronic lymphocytic leukemia (CLL): a study on 852 patients

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Recently, recurrent activating mutations of NOTCH1 have been reported in up to 12% of CLL patients, underlining the relevance of NOTCH1 mutations (NOTCH1mut) as an independent negative prognostic marker.1, 2, 3 NOTCH1mut in CLL are known to be located predominantly within the C-terminal PEST domain, frequently resulting in a truncated protein that is more stable than the wild-type one and activates the NOTCH1 signaling pathway.3

The aim of this study was to determine the frequency and prognostic impact of NOTCH1mut in CLL and to evaluate the range of mutational burden. We used the massively parallel amplicon next-generation deep-sequencing (NGS) technology (454 Life Sciences, Branford, CT, USA), enabling us to detect also low-level mutational clones, which have not been studied in detail yet. We here investigated a large unselected cohort of adult CLL patients for mutations in NOTCH1.