Abstract
FBXW7 missense mutations in T-ALL promote MYC stability and leukemia-initiating cell activity.
Major finding: FBXW7 missense mutations in T-ALL promote MYC stability and leukemia-initiating cell activity.
Concept: MYC occupancy at the promoters of NOTCH1 target genes enhances transcriptional activation.
Impact: BET bromodomain inhibitors that inhibit MYC may target leukemia-initiating cells and suppress T-ALL.
Heterozygous missense mutations in the gene encoding the ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7) are found in approximately 20% of T-cell acute lymphoblastic leukemias (T-ALL) and frequently co-occur with activating NOTCH1 mutations. To evaluate the role of FBXW7 missense mutations in leukemogenesis, King and colleagues conditionally expressed the most common FBXW7 mutation in the mouse hematopoietic system. Fbxw7-mutant hematopoietic stem cells showed an increased capacity for self-renewal in association with significantly higher protein levels of MYC, a known FBXW7 substrate and oncogenic driver of T-ALL. In vitro assays showed that the FBXW7 missense mutation prevents FBXW7 from binding and ubiquitinating MYC and thus increases MYC stability. Although the heterozygous Fbxw7 mutation alone was not sufficient to induce leukemia, expression of the Fbxw7 mutant significantly accelerated T-ALL induced by mutational activation of Notch1. Fbxw7 mutation led to a more than 10-fold increase in the frequency of leukemia-initiating cells (LIC), which were distinguished by high MYC protein levels and a MYC-driven gene expression signature. LICs in Notch1-driven T-ALL were also dependent on MYC for survival, suggesting that use of pharmacologic agents that suppress MYC expression might target T-ALL LICs. Indeed, BET bromodomain inhibitors blocked the growth of all human T-ALL cell lines tested and significantly slowed T-ALL progression in vivo. RNA and chromatin immunoprecipitation sequencing showed that almost half of NOTCH1 target gene promoters are occupied by MYC and that MYC occupancy is associated with significantly higher NOTCH1 target gene expression. These findings suggest a model in which stabilization of MYC in the context of FBXW7 missense mutation cooperates with activated NOTCH1 to increase the expression of leukemogenic genes and provide a rationale for clinical evaluation of BET bromodomain inhibitors in T-ALL.
