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Accession IconGSE87865

AKR1C enzymes sustain therapy resistance in pediatric T-ALL

Organism Icon Homo sapiens
Sample Icon 54 Downloadable Samples
Technology Badge Icon Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)

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Although intensification of chemotherapy approaches considerably increased the outcome of pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) patients, a subgroup of them still experience treatment failure and relapse. In this context, we hypothesized that the Nrf2 signalling and its downstream effectors could be involved in sustain therapy resistance in T-ALL, as previously reported in other cancers. Indeed, in this study we identified the Aldo-Keto Reductase (AKR) enzymes AKR1C1-3, as over-expressed in T-ALL samples from therapy-resistant patients, demonstrating their fundamental role in the control of the response to vincristine (VCR) treatment. In particular, we evidence that the modulation of AKR1C1-3 gene expression and activity is sufficient to strongly affect the sensitivity of T-ALL cell lines and primary cells to VCR treatment, but not to daunorubicin, cytarabine or L-asparaginase. Moreover, we found a correlation between the degree of VCR response and the amount of AKR1Cs expression in patient-derived T-ALL xenografts. Interestingly, we show that daunorubicin and cytarabine are able to induce the over-activation of AKR1C enzymes, thus establishing a potential resistance loop generated by the combination of these drugs during T-ALL treatment.
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