NOTCH1 encodes a member of the NOTCH family of proteins, which is a group of transmembrane receptors involved in the Notch signaling pathway. Notch signaling regulates cell fate decisions during development, and plays a crucial role in T cell development. Activating mutations of NOTCH1 including missense mutations and inframe inserstions/deletions in the heterodimerization(HD) domains either alone or together with missense, nonsense or frameshift (in/del) mutations in the C terminal PEST domain have been described in approximately 50% of cases of T-ALL. The HD domain or PEST domain mutations may occur together in cis (on the same allele) in ALL. NOTCH1 mutations are very rare in AML. However, NOTCH1 mutations are present in about 27% patients with T-myeloid mixed-phenotypeacute leukemia. The potential utility of therapeutic targeting of activating NOTCH1 mutations in these diseases remains to be elucidated.

NOTCH1 mutations have also recently been reported in approximately 10% of chronic lymphocytic leukemia and are typically PEST domain mutations in that disease. In CLL, NOTCH1 mutations and tend to be exlusive of SF3B1 mutations and possibly TP53 mutations, although some studies demonstrate that NOTCH1 mutations are associated with mutations of TP53. In CLL, the presence of NOTCH1 mutations has been associated with trisomy 12 and aggressive biologic features(CD38+, ZAP70+, unmutated IgH variable region) and adverse prognosis in some settings. The potential utility of therapeutic targeting of activating NOTCH1 mutations in these diseases remains to be elucidated.