Inhibition of ubiquitin-specific protease 7 sensitizes acute myeloid leukemia to chemotherapy

• DOI: 10.1038/s41375-020-0878-x
• Publication Date: 2020-05-23T18:02:33Z
• Authors: Maëlle Cartel; Pierre-Luc Mouchel; Mathilde Gotanègre; Laure David; Sarah Bertoli; Véronique Mansat-...; Arnaud Besson; Jean-Emmanuel Sarry; Stéphane Manenti; Christine Didier
• Keywords: Male; Antimetabolites, Antineoplastic; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Apoptosis; Mice, SCID; Article; Mice; 03 medical and health sciences; [SDV.CAN] Life Sciences [q-bio]/Cancer; Mice, Inbred NOD; Biomarkers, Tumor; Animals; Humans; RNA, Small Interfering; Cell Proliferation; 0303 health sciences; [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology; Gene Expression Profiling; Cytarabine; Middle Aged; Prognosis; 3. Good health; Gene Expression Regulation, Neoplastic; Leukemia, Myeloid, Acute; Drug Resistance, Neoplasm; Female; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Signal Transduction

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, single-cell 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.