The observations that different driver mutations are preferentially associated with different cytogenetic alterations strongly suggest that different alterations can cooperate to drive leukemogenesis and the clinical heterogeneity of the disease seems to reflect a different pathogenesis. in CLL, and indicate that activated NOTCH1 signaling and defects in the splicing machinery play a prominent role in the development of specific subsets of CLL (Physique 1).1,2 Open in a separate window Determine 1 Schematic representation of the NOTCH1 receptor. The extracellular domain name of NOTCH1 consists of 36 epidermal growth factor-like repeats (EGFR) followed by 3 cysteine-rich lin12/Notch repeats (LNR) and the heterodimerization domain name (HD). Upon transport to the plasmamembrane, NOTCH1 is usually cleaved in two models, which are kept together by interactions between the HD domains. Upon binding of the ligand, NOTCH1 is usually further cleaved by the gamma-secretase complex, resulting in release of the intra-cellular part (ICN1). ICN1 can then move to the nucleus where it functions in a transcriptional complex. ICN1 BPTU contains the RAM domain name (R), ankyrine repeats, transactivation domain name (TAD) and the PEST sequence that tags ICN1 for degradation by FBXW7. S2: proteolitic site for Metalloprotease; S3: gamma-secretase cleavage site. Activation of NOTCH1 in leukemia was first discovered through the analysis of the chromosomal translocation t(7;9)(q34;q34.3) in patients with T-cell acute lymphoblastic leukemia (T-ALL). Later, activating mutations in NOTCH1 were discovered in over 50% of T-ALL patients (Table 1). NOTCH (NOTCH1, NOTCH2, NOTCH3, NOTCH4) receptors are a family of transmembrane proteins expressed by cells of different tissues that function both as cell surface receptors and transcription regulators. Regulating a delicate balance of intracellular signals, they critically tune differentiation and proliferation processes and it is not surprising that alterations in NOTCH signaling have been reported in different diseases including hematologic and solid malignancies.11 Table 1 Reported NOTCH1 mutations in chronic lymphocytic leukemia. Open in a separate windows Constitutive activation of NOTCH1 signaling was also observed in CLL cells and was implicated in apoptosis resistance and increased survival of CLL cells.13 Recently, using next-generation sequencing technologies, different groups discovered that 4% of CLL patients also harbor mutations (Table 1), indicating that mutations could be one of the mechanisms explaining NOTCH activation in this disease.3C5,14 Different to T-ALL, the mutations almost exclusively occur in exon 34 and usually generate a premature stop codon resulting in a constitutively active and more stable NOTCH1 protein lacking the C-terminal PEST domain name. A recurrent CT deletion (p.P2515fs4) was found in around 80% of NOTCH1 mutation positive CDC14A BPTU CLL cases, and a PCR based strategy has been designed for its rapid detection.6 Although not frequent in unselected CLL at diagnosis, the mutations emerged as a recurrent target of genetic alteration in a specific group of patients and/or in a specific phase of disease. In fact, the first studies reported a high frequency of mutations in IGVH unmutated cases and in aggressive clinical phases of CLL as chemorefractory and disease progression towards transformation into Richters syndrome. A significant adverse impact on outcome has also been reported independently of other clinico-biological features, including alterations and unmutated genes, as NOTCH1 positive patients showed a significantly shorter overall survival, a shorter time to progression and a high risk of RS.4C6,14 Analyses on larger number of patients and on specific subgroups of patients have now documented a particularly high frequency of NOTCH1 mutation in CLL cases harboring trisomy 12 (+12), one of the cytogenetic alterations recurrently observed in CLL and classically associated with an BPTU intermediate prognosis.15 In this issue of Haematologica, Del Giudice and colleagues document a high frequency of NOTCH1 mutations in CLL cases harboring trisomy 12 as the sole cytogenetic abnormality (30%).7 Importantly, this study also reveals a significant shortening of survival in the NOTCH1 mutation BPTU positive patients, refining the intermediate prognosis of CLL cases with trisomy 12. Moreover, this study highlights that the presence of NOTCH1 mutations in +12 CLL cases is usually associated with a peculiar gene-expression profile characterized by an overrepresentation of cell cycle related genes that are located on chromosome 12. Similarly, Balatti reported enrichment for NOTCH1 mutations (around 42%) in IGVH unmutated/ZAP70+ CLL patients harboring trisomy 12, and a much lower frequency (4%) in unmutated/ZAP70+ cases without trisomy 12.8 Interestingly, in addition to NOTCH1 mutations, an exome sequencing study of 91 CLL cases also identified mutations in FBXW7, a negative regulator of NOTCH1.9 These mutations were also associated with trisomy 12 supporting the theory of a cooperation between NOTCH1 alterations and trisomy 12, and suggesting that.
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