Authors:
Beesley AH, Firth MJ, Anderson D, Samuels AL, Ford J, Kees UR
Authors notes:
Cancer Research. 2013;73(9):2749-2759
Keywords:
T-cell acute lymphoblastic leukaemia, 6-mercaptopurine, drug resistance patient outcome, drug-gene modelling, patient stratification
Abstract:
Patients relapsing with T-cell acute lymphoblastic leukemia (T-ALL) face a dismal outcome.
The aim of this study was to identify new markers of drug resistance and clinical response in T-ALL.
We measured gene expression and drug sensitivity in 15 pediatric T-ALL cell lines to find signatures predictive of resistance to 10 agents used in therapy.
These were used to generate a model for outcome prediction in patient cohorts using microarray data from diagnosis specimens.
In three independent T-ALL cohorts, the 10-drug model was able to accurately identify patient outcome, indicating that the in vitro-derived drug-gene profiles were clinically relevant.
Importantly, predictions of outcome within each cohort were linked to distinct drugs, suggesting that different mechanisms contribute to relapse.
Sulfite oxidase (SUOX) expression and the drug-transporter ABCC1 (MRP1) were linked to thiopurine sensitivity, suggesting novel pathways for targeting resistance.
This study advances our understanding of drug resistance in T-ALL and provides new markers for patient stratification.
The results suggest potential benefit from the earlier use of 6-mercaptopurine in T-ALL therapy or the development of adjuvants that may sensitize blasts to this drug.