FBXW7 (FBW7) mutations are found in ~20% of T-cell acute lymphoblastic leukemia samples. Although a homozygous FBXW7 deletion has been reported, mutations found in FBXW7 are predominantly dominant negative missense mutations that target one of the three highly conserved arginine residues in the WD repeats of FBXW7 (arginines at positions 465, 479 and 505 in the alpha isoform of FBXW7 i.e. positions 347, 361 and 387 in the gamma isoform of FBXW7, as seen in FBXW7alpha R465C i.e. FBXW7gamma R347C, FBXW7alpha R465H i.e. FBXW7gamma R347H, FBXW7alpha R479Q i.e. FBXW7gamma R361Q, FBXW7alpha R505C i.e. FBXW7gamma R387C, and FBXW7alpha R505L i.e. FBXW7gamma R387L). These three arginine residues are part of the FBXW7 substrate binding pocket and each one of them contacts the phosphorylated threonine residue in the conserved substrate phosphodegron region (Orlicky et al. 2003). FBXW7 mutations are mutually exclusive with NOTCH1 PEST domain mutations (Thompson et al. 2007, O'Neil et al. 2007).
Besides targeting NICD1 for degradation, FBXW7 also binds and promotes ubiquitination and proteasome-mediated degradation of MYC (Welcker et al. 2004a, Welcker et al. 2004b), a direct NOTCH1 target, as well as cyclin E (Koepp et al. 2001) and JUN (Wei et al. 2005). T-ALL cell lines with FBXW7 mutations are resistant to gamma-secretase inhibitors (GSIs) (Thompson et al. 2007, O'Neil et al. 2007), and in T-ALL patient samples FBXW7 mutations are more frequently detected at relapse than at primary diagnosis (Thompson et al. 2007). The resistance to GSIs in FBXW7 mutant T-ALL cells may be due to sustained MYC activity (Thomspon et al. 2007, O'Neil et al. 2007).