Chronic Lymphocytic Leukemia

Trisomy 12 represents the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL) (1520% of cases) and often (approx. 60% of cases) occurs as the sole cytogenetic lesion. Within the hierarchical model of genetic subgroups commonly used in clinical practice, +12 as single aberration confers an intermediate prognostic risk, with a median time to progression of 33 months and a median overall survival (OS) of 114 months. The NOTCH1 gene has been shown to have an essential biological role in hematopoiesis. Following the pivotal study that identified NOTCH1 mutations in CLL and provided initial evidence on the unfavorable clinical outcome associated with NOTCH1 alterations, two independent studies of the CLL coding genome have recently identified activating mutations of the NOTCH1 gene in approximately 10% of CLL at diagnosis. The prevalence of NOTCH1 mutations increases with disease aggressiveness. At diagnosis, NOTCH1 mutations show an adverse impact on outcome, confirmed in at least four series, and act independently of other clinico-biological features, including TP53 disruption. Among CLL cytogenetic subgroups, NOTCH1 mutations are distributed in a mutually exclusive fashion with TP53 disruption and are enriched in CLL carrying +12, where they recur in approximately 25% of patients. Based on the emerging association between NOTCH1 alterations and +12, we investigated NOTCH1mutations in a series of untreated +12 CLL. We observed that in these patients, NOTCH1 mutations: i) cluster within cases with no additional cytogenetic abnormalities; ii) induce a particular transcriptional profile; and iii) refine outcome prediction. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL