AKR1C enzymes sustain therapy resistance in paediatric T-ALL

Roberta Bortolozzi, Silvia Bresolin, Elena Rampazzo, Maddalena Paganin, Francesca Maule, Elena Mariotto, Daniele Boso, Sonia Minuzzo, Valentina Agnusdei, Giampietro Viola, Geertruy Te Kronnie, Giovanni Cazzaniga, Giuseppe Basso, Luca Persano

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)985-994
Number of pages10
JournalBritish Journal of Cancer
Volume118
Issue number7
DOIs
Publication statusPublished - Apr 2018

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    Bortolozzi, R., Bresolin, S., Rampazzo, E., Paganin, M., Maule, F., Mariotto, E., Boso, D., Minuzzo, S., Agnusdei, V., Viola, G., Te Kronnie, G., Cazzaniga, G., Basso, G., & Persano, L. (2018). AKR1C enzymes sustain therapy resistance in paediatric T-ALL. British Journal of Cancer, 118(7), 985-994. https://doi.org/10.1038/s41416-018-0014-0