• What is NOTCH1?
  • NOTCH1 in Chronic Lymphocytic Leukemia
  • Clinical Trials


Notch 1 (NOTCH1) is a gene that encodes a transmembrane protein that functions in multiple developmental processes and the interactions between adjacent cells. The transmembrane protein also functions as a receptor for membrane bound ligands. Fusions, missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions and insertions are observed in cancers such as esophageal cancer, hematopoietic and lymphoid cancers, and stomach cancer.

Last Updated: July 1, 2015

NOTCH1 in Chronic Lymphocytic Leukemia

NOTCH1 can be altered in several different ways in chronic lymphocytic leukemia (CLL), including insertions, duplications, deletions, frameshift, missense, and nonsense mutations, although NOTCH1 mutation events are predominated by frameshift and nonsense mutations in a hotspot in exon 34 (Chiaretti et al. 2014; Gianfelici 2012; Puente et al. 2011; Rossi et al. 2012a; Rossi and Gaidano 2012; Zent and Burack 2014). Indeed, the exon 34 frameshift deletion c.7544_7545delCT (p.Pro2514Argfs*4) has been reported to account for about ~80-94% of NOTCH1 mutations in CLL (Baliakas et al. 2015; Rossi et al. 2012a; COSMIC). Exon 34 mutations in NOTCH1 in CLL primarily result in premature protein truncation, generating a NOTCH1 protein lacking the C-terminal PEST domain, where inactivating phosphorylation of NOTCH1 can occur to turn off NOTCH1 signaling; truncated NOTCH1 is thus more stable and constitutively active (Arruga et al. 2014; Gianfelici 2012; Puente et al. 2011; Rossi and Gaidano 2012; Zent and Burack 2014). The NOTCH1 protein is a single-pass transmembrane receptor that acts as a ligand-activated transcription factor to tune cell differentiation and proliferation processes (Arruga et al. 2014; Gianfelici 2012; Guruharsha, Kankel, and Artavanis-Tsakonas 2012; Lobry, Oh, and Aifantis 2011; Lobry et al. 2014). In the lymphoid system, NOTCH1 signaling directs hematopoetic progenitor cells toward a T-cell fate and prevents differentiation to B-cells; in mature B-cells, NOTCH1 signaling results in differentiation toward antibody-secreting cells (Rossi and Gaidano 2012). The downstream consequences of constitutively active NOTCH1 include enhanced activity of both the canonical and non-canonical NF-κB and resistance to apoptosis (Rosati et al. 2009; Rossi and Gaidano 2012; Xu et al. 2015; Zent and Burack 2014).

Clinical Impact

NOTCH1 lesions are much more prevalent after disease progression to Richters transformation (31.0%) and in chemorefractory CLL (20.4–20.8% of cases) relative to newly diagnosed CLL (8.3%–11.3% of cases) (Fabbri et al. 2011; Rossi et al. 2012a), although variable rates of NOTCH1 mutation in CLL have been reported in other studies (1.5%–18%); these variations are likely in part due differences between cohorts relative to time since diagnosis, disease stage, and other genetic alterations enriched in the study (Balatti et al. 2012; Baliakas et al. 2015; Chiaretti et al. 2014; Cortese et al. 2014; Di Ianni et al. 2009; Jeromin et al. 2014; Lionetti et al. 2014; López et al. 2012; Puente et al. 2011; Schnaiter et al. 2013; Shedden et al. 2012; Sutton et al. 2015; Weissmann et al. 2013; Willander et al. 2013; Xia et al. 2015). COSMIC reports an overall mutation rate for NOTCH1 in combined studies of 10.3% (COSMIC). Additionally, NOTCH1 lesions are associated with high risk CLL, and NOTCH1 lesions are independently predictive of prognosis and progression to the more severe Richters syndrome. The time to first treatment was significantly shorter in patients with NOTCH1 mutations as compared to patients with wild-type (Nadeu et al. 2016). Patients with NOTCH1 mutations display poor survival outcomes similar to those of patients with TP53 disruption (Baliakas et al. 2015; Cortese et al. 2014; Fabbri et al. 2011; Falisi et al. 2014; del Guidice 2012; Jeromin et al. 2014; Oscier et al. 2013; Puente et al. 2011; Rossi et al. 2012a; Rossi et al. 2012b; Villamor et al. 2013; Weissmann et al. 2013; Willander et al. 2013; Xia et al. 2015). Other studies have found no association between NOTCH1 lesions and response to treatment (Chiaretti et al. 2014; Dreger et al. 2013; Edelmann et al. 2012).

Evidence indicates that NOTCH1 mutations can occur in the context of other genetic markers. For instance, NOTCH1 mutations are associated with trisomy 12 (Balatti et al. 2012; Baliakas et al. 2015; Chiaretti et al. 2014Falisi et al. 2014del Guidice 2012; Jeromin et al. 2014; Puiggros, Blanco, and Espinet 2014; Rossi et al. 2012a; Rossi et al. 2013; Villamor et al. 2013; Xia et al. 2015) and with 14q deletions (Cosson et al. 2014). Additionally, NOTCH1 lesions are associated with CD38 and ZAP70 expression, markers of poor prognosis (Chiaretti et al. 2014; ten Hacken and Burger 2016; Oscier et al. 2013; Villamor et al. 2013). NOTCH1 mutation appears to correlate with unmutated Ig heavy-chain variable region genes (IGHVs) (U-CLL), a more aggressive type of CLL than the mutated counterpart (Baliakas et al. 2015; Chiaretti et al. 2014; Gianfelici 2012; Jeromin et al. 2014; Puente et al. 2011; Villamor et al. 2013). Further, NOTCH1 mutations have been shown to inversely correlate with TP53 disruption and 11q deletion (del Guidice 2012; Rossi et al. 2012a). Another study of a Scandinavian cohort of 364 patients found that NOTCH1 lesions are inversely correlated with mutations in SF3B1, BIRC3, and TP53 (Cortese et al. 2014). However, other studies demonstrate positive correlation between NOTCH1 lesions and TP53-mutated CLL (Baliakas et al. 2015; Weissmann et al. 2013).

Preclinical evidence suggests that γ-secretase inhibitors, which prevent cleavage of NOTCH1 to release the intracellular domain responsible for its transcription factor activity, may be effective in CLL harboring NOTCH1 lesions (López-Guerra et al. 2015). Due to the toxicity observed in some γ-secretase inhibitors in the clinical setting, a number of other compounds targeting the NOTCH1 pathway at other sites are under development (Andersson and Lendahl 2014; Groth and Fortini 2012).

Contributors: Nishitha Reddy, M.B.B.S., MSCI

Suggested Citation: Reddy, N. 2016. NOTCH1 in Chronic Lymphocytic Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/chronic-lymphocytic-leukemia/notch1/ (Updated February 15).

Last Updated: February 15, 2016

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