FBXW7 in leukemia: A critical regulator of oncogenic stability and a potential therapeutic target

F-Box and WD repeat domain-containing 7 (FBXW7) is a key tumor suppressor and substrate-recognition component of the Skp1-Cullin-F-box E3 ubiquitin ligase complex, responsible for targeting several crucial oncogenic proteins for proteasomal degradation. It plays a significant role in preventing the accumulation of pro-oncogenic substrates, thereby maintaining cellular homeostasis. Mutations or inactivation of FBXW7 disrupt these processes, leading to the stabilization of oncogenic proteins such as c-Myc, Notch, myeloid cell leukemia 1, and cyclin E, which drive malignant transformation in several cancers, including hematological malignancies such as T-cell and B-cell acute lymphoblastic leukemia. These mutations contribute to resistance to apoptosis, dysregulated proliferation, and poor prognosis, highlighting FBXW7 as a critical factor in leukemia pathogenesis and a promising therapeutic target. Here, we review FBXW7’s structure and function, its key substrates in leukemia, and therapeutic strategies that restore its function or target the oncogenic pathways it regulates. Advances in genome-wide CRISPR screenings and proteomics have further illuminated FBXW7’s involvement in multidrug resistance, positioning it as a biomarker and therapeutic target for improving leukemia treatment outcomes.