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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.

SUBMITTER: Meyer JA

PROVIDER: S-EPMC3681285 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.

Meyer Julia A JA Wang Jinhua J Hogan Laura E LE Yang Jun J JJ Dandekar Smita S Patel Jay P JP Tang Zuojian Z Zumbo Paul P Li Sheng S Zavadil Jiri J Levine Ross L RL Cardozo Timothy T Hunger Stephen P SP Raetz Elizabeth A EA Evans William E WE Morrison Debra J DJ Mason Christopher E CE Carroll William L WL

Nature genetics 20130203 3

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 dia ...[more]

PMID: 23377183

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Project description:Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers.There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results.Patients-We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis-Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations-Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835) using polymerase chain reaction methods.Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22), t(12;21), and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7%) and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22), MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group (P = .031).The event-free survival was also found to be worse (P = .040).Our data are in accordance with those published previously, confirming the overall frequency of cytogenetic abnormalities and their prognostic relevance.

Dataset Information

Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.

Publications

Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.

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