Mutations of FBW7 WD40 domain residues that contribute to either transforming activity or reducing substrate NOTCH1 binding/degradation are depicted as red spheres (R465, G423, W425, R479, R505 in CLL; W425, S462, H468, R505, D527 in ATL; G423, R505, W486 in melanoma). The gene discussed is NOTCH1; the disease is B-cell chronic lymphocytic leukemia.