Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia

Julia A. Meyer, Jinhua Wang, Laura E. Hogan, Jun J. Yang, Smita Dandekar, Jay P. Patel, Zuojian Tang, Paul Zumbo, Sheng Li, Jiri Zavadil, Ross L. Levine, Timothy Cardozo, Stephen P. Hunger, Elizabeth A. Raetz, William E. Evans, Debra J. Morrison, Christopher E. Mason, William L. Carroll

Research output: Contribution to journalArticlepeer-review

188 Scopus citations

Abstract

Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.

Original languageEnglish (US)
Pages (from-to)290-294
Number of pages5
JournalNature Genetics
Volume45
Issue number3
DOIs
StatePublished - Mar 2013

Bibliographical note

Funding Information:
We would like to thank the members of the Carroll laboratory as well as L.B. Gardner, M. Karajannis and I. Osman for their critical review of the manuscript. We gratefully acknowledge the Children’s Oncology Group (COG) for patient specimens, the New York University Genome Technology Center for expert assistance with Illumina (B. Baysa) and Roche 454 (E. Venturini) deep-sequencing experiments (supported in part by US National Institutes of Health/National Center for Research Resources (NIH/NCRR) grant S10 RR026950-01), P. Grace, J.D. Ernst and M.R. Phillips (New York University School of Medicine) for expression and lentiviral vectors and F. Tsai, M.R. Phillips and S.M. Brown for technical guidance. This work was supported by US NIH grants R01 CA140729 and R21 CA152838-02 to W.L.C. and New York University Cancer Center Support Grant 5 P30 CA16087-30 in collaboration with the New York University Genome Technology Center. Additional support was provided by grants from the National Cancer Institute to COG, including U10 CA98543 (COG Chair’s grant), U10 CA98413 (COG Statistical Center) and U24 CA114766 (COG Specimen Banking). J.A.M. is supported by NIH grant T32 CA009161. L.E.H. was supported by the American Society of Hematology and St. Baldrick’s Foundation. S.P.H. is the Ergen Family Chair in Pediatric Cancer.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

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