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.

Bortolozzi, R., Bresolin, S., Rampazzo, E., Paganin, M., Maule, F., Mariotto, E., et al. (2018). AKR1C enzymes sustain therapy resistance in paediatric T-ALL /631/67/1059/2326 /631/67/1990/283/2125 article. BRITISH JOURNAL OF CANCER, 118(7), 985-994 [10.1038/s41416-018-0014-0].

AKR1C enzymes sustain therapy resistance in paediatric T-ALL /631/67/1059/2326 /631/67/1990/283/2125 article

Cazzaniga, G;
2018

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.
Articolo in rivista - Articolo scientifico
Oncology; Cancer Research
English
2018
118
7
985
994
reserved
Bortolozzi, R., Bresolin, S., Rampazzo, E., Paganin, M., Maule, F., Mariotto, E., et al. (2018). AKR1C enzymes sustain therapy resistance in paediatric T-ALL /631/67/1059/2326 /631/67/1990/283/2125 article. BRITISH JOURNAL OF CANCER, 118(7), 985-994 [10.1038/s41416-018-0014-0].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/226360
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