Drug―Gene Modeling in Pediatric T-Cell Acute Lymphoblastic Leukemia Highlights Importance of 6-Mercaptopurine for Outcome

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 9; pp. 2749 - 2759
• Main Authors: BEESLEY, Alex H, FIRTH, Martin J, ANDERSON, Denise, SAMUELS, Amy L, FORD, Jette, KEES, Ursula R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2013
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Child; Cohort Studies; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; Follow-Up Studies; Gene Expression Profiling; Genetic Therapy - methods; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mercaptopurine - therapeutic use; Models, Statistical; Multidrug Resistance-Associated Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Pharmacogenetics; Pharmacology. Drug treatments; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Remission Induction; Sulfite Oxidase - metabolism; Treatment Outcome; Tumors; Human; Antineoplastic agent; Drug; Pediatrics; Purine derivatives; Prognosis; Thiopurine derivatives; Malignant hemopathy; Modeling; Antimetabolic; Gene; Lymphoproliferative syndrome; Genetics; Child; Cancer; Mercaptopurine; T cell acute lymphoblastic leukemia
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3852

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. The methodology developed in this study could be applied to other cancers to achieve patient stratification at the time of diagnosis.