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Clinical Studies

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

Alex H. Beesley, Martin J. Firth, Denise Anderson, Amy L. Samuels, Jette Ford and Ursula R. Kees
Alex H. Beesley
Authors' Affiliations: Division of Children's Leukaemia and Cancer Research, and Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
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Martin J. Firth
Authors' Affiliations: Division of Children's Leukaemia and Cancer Research, and Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
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Denise Anderson
Authors' Affiliations: Division of Children's Leukaemia and Cancer Research, and Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
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Amy L. Samuels
Authors' Affiliations: Division of Children's Leukaemia and Cancer Research, and Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
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Jette Ford
Authors' Affiliations: Division of Children's Leukaemia and Cancer Research, and Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
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Ursula R. Kees
Authors' Affiliations: Division of Children's Leukaemia and Cancer Research, and Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
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DOI: 10.1158/0008-5472.CAN-12-3852 Published May 2013
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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. The methodology developed in this study could be applied to other cancers to achieve patient stratification at the time of diagnosis. Cancer Res; 73(9); 2749–59. ©2013 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received October 8, 2012.
  • Revision received January 20, 2013.
  • Accepted February 9, 2013.
  • ©2013 American Association for Cancer Research.
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Cancer Research: 73 (9)
May 2013
Volume 73, Issue 9
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Drug–Gene Modeling in Pediatric T-Cell Acute Lymphoblastic Leukemia Highlights Importance of 6-Mercaptopurine for Outcome
Alex H. Beesley, Martin J. Firth, Denise Anderson, Amy L. Samuels, Jette Ford and Ursula R. Kees
Cancer Res May 1 2013 (73) (9) 2749-2759; DOI: 10.1158/0008-5472.CAN-12-3852

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Drug–Gene Modeling in Pediatric T-Cell Acute Lymphoblastic Leukemia Highlights Importance of 6-Mercaptopurine for Outcome
Alex H. Beesley, Martin J. Firth, Denise Anderson, Amy L. Samuels, Jette Ford and Ursula R. Kees
Cancer Res May 1 2013 (73) (9) 2749-2759; DOI: 10.1158/0008-5472.CAN-12-3852
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