It is perhaps the most widely studied F-box protein due to its role in a panel of both normal and malignant cellular processes [187,188]; in fact, mutations of the FBXW7 gene have been identified in more than 30% of pediatric T-ALL [188,189] and several other hematological and non-hematological diseases [190,191,192,193,194] These mutations disrupt the direct interaction between FBXW7 and NICD and extend the half-life of NICD, thus mimicking the effects of canonical NOTCH1 mutations (Figure 4B). The gene discussed is NOTCH1; the disease is acute lymphoblastic leukemia.