期刊
NATURE GENETICS
卷 45, 期 3, 页码 290-294出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2558
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资金
- US National Institutes of Health/National Center for Research Resources (NIH/NCRR) grant [S10 RR026950-01]
- US NIH [R01 CA140729, R21 CA152838-02]
- New York University Cancer Center Support Grant [5 P30 CA16087-30]
- New York University Genome Technology Center
- National Cancer Institute [U10 CA98543, U10 CA98413, U24 CA114766]
- NIH grant [T32 CA009161]
- American Society of Hematology
- St. Baldrick's Foundation
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance(1,2). 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.
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