Model of sequential genetic alterations in T-ALL. After ionizing radiation exposure, Tp53 levels increased as a result of DNA damage, which elicited an increase in Fbxw7 levels and a subsequent reduction in overall Notch1 activity. Genetic alterations opposing these changes arose sequentially in Notch1, Fbxw7, and Tp53 to yield T-ALL formation (A). In contrast, thymocytes with only 1 copy of Fbxw7 bypassed Notch1 mutations during malignant transformation (B). Paradoxically, thymocytes entirely lacking Tp53 underwent malignant transformation without Fbxw7 alteration but still displayed Notch1 mutations (C).