Whereas activating mutations in NOTCH1 have been identified in T-cell acute lymphoblastic leukemia and breast cancer [38–40], a tumor suppressor role for NOTCH signaling has been suggested in tumor types such as chronic myelomonocytic leukemia (CMML) [41], HNSCC [29] and lung SCC [42]. This evidence concerns the gene NOTCH1 and head and neck squamous cell carcinoma.