AKR1C enzymes sustain therapy resistance in paediatric T-ALL

Background Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previ...

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Bibliographic Details
Published in:British journal of cancer 2018-04, Vol.118 (7), p.985-994
Main Authors: Bortolozzi, Roberta, Bresolin, Silvia, Rampazzo, Elena, Paganin, Maddalena, Maule, Francesca, Mariotto, Elena, Boso, Daniele, Minuzzo, Sonia, Agnusdei, Valentina, Viola, Giampietro, te Kronnie, Geertruy, Cazzaniga, Giovanni, Basso, Giuseppe, Persano, Luca
Format: Article
Language:English
Subjects:
631/67/1059/2326
631/67/1990/283/2125
Acute lymphoblastic leukemia
Aldo-keto reductase
Biomedical and Life Sciences
Biomedicine
Cancer Research
Chemotherapy
Drug Resistance
Enzymes
Epidemiology
Gene silencing
Leukemia
Lymphatic leukemia
Lymphocytes T
Molecular Medicine
Oncology
Patients
Pediatrics
Solid tumors
Tumors
Vincristine
Xenografts
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Summary:Background Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors. Methods Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches. Results We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment. Conclusions Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-018-0014-0