title: Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.
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.
authors: New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.
authors: Julia A
authors: JA
authors: Meyer
authors: Jinhua
authors: J
authors: Wang
authors: Laura E
authors: LE
authors: Hogan
authors: Jun J
authors: JJ
authors: Yang
authors: Smita
authors: S
authors: Dandekar
authors: Jay P
authors: JP
authors: Patel
authors: Zuojian
authors: Z
authors: Tang
authors: Paul
authors: P
authors: Zumbo
authors: Sheng
authors: S
authors: Li
authors: Jiri
authors: J
authors: Zavadil
authors: Ross L
authors: RL
authors: Levine
authors: Timothy
authors: T
authors: Cardozo
authors: Stephen P
authors: SP
authors: Hunger
authors: Elizabeth A
authors: EA
authors: Raetz
authors: William E
authors: WE
authors: Evans
authors: Debra J
authors: DJ
authors: Morrison
authors: Christopher E
authors: CE
authors: Mason
authors: William L
authors: WL
authors: Carroll
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002648:Child; D019008:Drug Resistance, Neoplasm; D005091:Exons; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011487:Protein Conformation; D012008:Recurrence
chemical_list: D015720:5'-Nucleotidase; C508048:NT5C2 protein, human
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