Ablation of Fbxw7 Eliminates Leukemia-Initiating Cells by Preventing Quiescence

SummaryImatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML.

Graphical AbstractFigure optionsDownload high-quality image (232 K)Download as PowerPoint slideHighlights
► The Fbxw7–c-Myc axis is pivotal for maintenance of quiescence and stemness in LICs
► Combination of Fbxw7 ablation and anticancer drugs is effective for LIC eradication
► Fbxw7 deficiency affects LICs more than it does normal HSCs
► Downregulation of Fbxw7 is effective for eradication of human LICs