Inhibition of ubiquitin-specific protease 7 sensitizes acute myeloid leukemia to chemotherapy
Résumé
Resistance of acute myeloid leukemia (AML) to therapeutic agents is frequent. Consequently, the mechanisms leading to
this resistance must be understood and addressed. In this paper, we demonstrate that inhibition of deubiquitinylase
USP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases cell
death in AML. Transcriptomic dataset analyses reveal that a USP7 gene signature is highly enriched in cells from AML
patients at relapse, as well as in residual blasts from patient-derived xenograft (PDX) models treated with clinically relevant
doses of cytarabine, which indicates a relationship between USP7 expression and resistance to therapy. Accordingly, singlecell
analysis of AML patient samples at relapse versus at diagnosis showed that a gene signature of the pre-existing
subpopulation responsible for relapse is enriched in transcriptomes of patients with a high USP7 level. Furthermore, we
found that USP7 interacts and modulates CHK1 protein levels and functions in AML. Finally, we demonstrated that USP7
inhibition acts in synergy with cytarabine to kill AML cell lines and primary cells of patients with high USP7 levels.
Altogether, these data demonstrate that USP7 is both a marker of resistance to chemotherapy and a potential therapeutic
target in overcoming resistance to treatment.
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