Genetic variants in cytosolic 5́-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia

Amit K. Mitra, Kristine R. Crews, Stanley Pounds, Xueyuan Cao, Tanya Feldberg, Yogita Ghodke, Varsha Gandhi, William Plunkett, M. Eileen Dolan, Christine Hartford, Susana Raimondi, Dario Campana, James Downing, Jeffrey E. Rubnitz, Raul C. Ribeiro, Jatinder K. Lamba

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Cytosolic 5′-nucleotidase II (NT5C2) is involved in the development of 1-β-D-arabinofuranosylcytosine (ara-C) resistance and has been associated with clinical outcome in patients receiving ara-C-based chemotherapy. NT5C2 inactivates ara-C by dephosphorylating ara-C monophosphate to ara-C. In this study, we sequenced NT5C2 in genomic DNA samples from International HapMap project panels with European [Centre d'Etude du Polymorphisme Humain (CEU); n = 90] or African [Yoruba people in Ibadan, Nigeria (YRI); n = 90] ancestry. We identified 41 genetic variants [one insertion-deletion and 40 single nucleotide polymorphisms (SNPs)], including three nonsynonymous SNPs (Y3A, K47R, and Q136R). Twenty-five SNPs were novel and 16 overlapped with the HapMap data. Subjects with African ancestry had NT5C2 mRNA expression levels that was significantly higher than those with European ancestry (p = 0.005). Furthermore, there was a correlation between NT5C2 mRNA expression and ara-C sensitivity in CEU but not in YRI cell lines. None of the nonsynonymous SNPs demonstrated any effect on NT5C2 activity. The genotypes of several SNPs were significantly associated with NT5C2 mRNA expression and/or ara-C sensitivity in CEU cell lines, but very few were significant in YRI cell lines. Of most interest, SNPs (linkage disequilibrium group CEU.12) in the 5′-untranslated region were associated with NT5C2 expression and ara-C sensitivity in HapMap cell lines and with NT5C2 mRNA expression and ara-C sensitivity in diagnostic leukemic blasts from pediatric patients with acute myeloid leukemia. Functional genomics analysis demonstrated that the promoter SNP rs11191612 was associated with altered luciferase activation in reporter assays and altered DNA-protein binding in gel shift assays. These results suggest that genetic variations in NT5C2 influence its expression and, potentially, cellular responses to nucleoside analogs.

Original languageEnglish (US)
Pages (from-to)9-23
Number of pages15
JournalJournal of Pharmacology and Experimental Therapeutics
Volume339
Issue number1
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Fingerprint

HapMap Project
5'-Nucleotidase
Cytarabine
Acute Myeloid Leukemia
Single Nucleotide Polymorphism
Cell Line
Messenger RNA
5' Untranslated Regions
Linkage Disequilibrium
DNA-Binding Proteins
Nigeria
Genomics
Luciferases
Nucleosides
Gels
Genotype
Pediatrics
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Genetic variants in cytosolic 5́-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia. / Mitra, Amit K.; Crews, Kristine R.; Pounds, Stanley; Cao, Xueyuan; Feldberg, Tanya; Ghodke, Yogita; Gandhi, Varsha; Plunkett, William; Dolan, M. Eileen; Hartford, Christine; Raimondi, Susana; Campana, Dario; Downing, James; Rubnitz, Jeffrey E.; Ribeiro, Raul C.; Lamba, Jatinder K.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 339, No. 1, 01.10.2011, p. 9-23.

Research output: Contribution to journalArticle

Mitra, AK, Crews, KR, Pounds, S, Cao, X, Feldberg, T, Ghodke, Y, Gandhi, V, Plunkett, W, Dolan, ME, Hartford, C, Raimondi, S, Campana, D, Downing, J, Rubnitz, JE, Ribeiro, RC & Lamba, JK 2011, 'Genetic variants in cytosolic 5́-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia', Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 1, pp. 9-23. https://doi.org/10.1124/jpet.111.182873
Mitra, Amit K. ; Crews, Kristine R. ; Pounds, Stanley ; Cao, Xueyuan ; Feldberg, Tanya ; Ghodke, Yogita ; Gandhi, Varsha ; Plunkett, William ; Dolan, M. Eileen ; Hartford, Christine ; Raimondi, Susana ; Campana, Dario ; Downing, James ; Rubnitz, Jeffrey E. ; Ribeiro, Raul C. ; Lamba, Jatinder K. / Genetic variants in cytosolic 5́-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 339, No. 1. pp. 9-23.
@article{ccd0e76ae4c543a99c3561edab789d61,
title = "Genetic variants in cytosolic 5́-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia",
abstract = "Cytosolic 5′-nucleotidase II (NT5C2) is involved in the development of 1-β-D-arabinofuranosylcytosine (ara-C) resistance and has been associated with clinical outcome in patients receiving ara-C-based chemotherapy. NT5C2 inactivates ara-C by dephosphorylating ara-C monophosphate to ara-C. In this study, we sequenced NT5C2 in genomic DNA samples from International HapMap project panels with European [Centre d'Etude du Polymorphisme Humain (CEU); n = 90] or African [Yoruba people in Ibadan, Nigeria (YRI); n = 90] ancestry. We identified 41 genetic variants [one insertion-deletion and 40 single nucleotide polymorphisms (SNPs)], including three nonsynonymous SNPs (Y3A, K47R, and Q136R). Twenty-five SNPs were novel and 16 overlapped with the HapMap data. Subjects with African ancestry had NT5C2 mRNA expression levels that was significantly higher than those with European ancestry (p = 0.005). Furthermore, there was a correlation between NT5C2 mRNA expression and ara-C sensitivity in CEU but not in YRI cell lines. None of the nonsynonymous SNPs demonstrated any effect on NT5C2 activity. The genotypes of several SNPs were significantly associated with NT5C2 mRNA expression and/or ara-C sensitivity in CEU cell lines, but very few were significant in YRI cell lines. Of most interest, SNPs (linkage disequilibrium group CEU.12) in the 5′-untranslated region were associated with NT5C2 expression and ara-C sensitivity in HapMap cell lines and with NT5C2 mRNA expression and ara-C sensitivity in diagnostic leukemic blasts from pediatric patients with acute myeloid leukemia. Functional genomics analysis demonstrated that the promoter SNP rs11191612 was associated with altered luciferase activation in reporter assays and altered DNA-protein binding in gel shift assays. These results suggest that genetic variations in NT5C2 influence its expression and, potentially, cellular responses to nucleoside analogs.",
author = "Mitra, {Amit K.} and Crews, {Kristine R.} and Stanley Pounds and Xueyuan Cao and Tanya Feldberg and Yogita Ghodke and Varsha Gandhi and William Plunkett and Dolan, {M. Eileen} and Christine Hartford and Susana Raimondi and Dario Campana and James Downing and Rubnitz, {Jeffrey E.} and Ribeiro, {Raul C.} and Lamba, {Jatinder K.}",
year = "2011",
month = "10",
day = "1",
doi = "10.1124/jpet.111.182873",
language = "English (US)",
volume = "339",
pages = "9--23",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Genetic variants in cytosolic 5́-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia

AU - Mitra, Amit K.

AU - Crews, Kristine R.

AU - Pounds, Stanley

AU - Cao, Xueyuan

AU - Feldberg, Tanya

AU - Ghodke, Yogita

AU - Gandhi, Varsha

AU - Plunkett, William

AU - Dolan, M. Eileen

AU - Hartford, Christine

AU - Raimondi, Susana

AU - Campana, Dario

AU - Downing, James

AU - Rubnitz, Jeffrey E.

AU - Ribeiro, Raul C.

AU - Lamba, Jatinder K.

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Cytosolic 5′-nucleotidase II (NT5C2) is involved in the development of 1-β-D-arabinofuranosylcytosine (ara-C) resistance and has been associated with clinical outcome in patients receiving ara-C-based chemotherapy. NT5C2 inactivates ara-C by dephosphorylating ara-C monophosphate to ara-C. In this study, we sequenced NT5C2 in genomic DNA samples from International HapMap project panels with European [Centre d'Etude du Polymorphisme Humain (CEU); n = 90] or African [Yoruba people in Ibadan, Nigeria (YRI); n = 90] ancestry. We identified 41 genetic variants [one insertion-deletion and 40 single nucleotide polymorphisms (SNPs)], including three nonsynonymous SNPs (Y3A, K47R, and Q136R). Twenty-five SNPs were novel and 16 overlapped with the HapMap data. Subjects with African ancestry had NT5C2 mRNA expression levels that was significantly higher than those with European ancestry (p = 0.005). Furthermore, there was a correlation between NT5C2 mRNA expression and ara-C sensitivity in CEU but not in YRI cell lines. None of the nonsynonymous SNPs demonstrated any effect on NT5C2 activity. The genotypes of several SNPs were significantly associated with NT5C2 mRNA expression and/or ara-C sensitivity in CEU cell lines, but very few were significant in YRI cell lines. Of most interest, SNPs (linkage disequilibrium group CEU.12) in the 5′-untranslated region were associated with NT5C2 expression and ara-C sensitivity in HapMap cell lines and with NT5C2 mRNA expression and ara-C sensitivity in diagnostic leukemic blasts from pediatric patients with acute myeloid leukemia. Functional genomics analysis demonstrated that the promoter SNP rs11191612 was associated with altered luciferase activation in reporter assays and altered DNA-protein binding in gel shift assays. These results suggest that genetic variations in NT5C2 influence its expression and, potentially, cellular responses to nucleoside analogs.

AB - Cytosolic 5′-nucleotidase II (NT5C2) is involved in the development of 1-β-D-arabinofuranosylcytosine (ara-C) resistance and has been associated with clinical outcome in patients receiving ara-C-based chemotherapy. NT5C2 inactivates ara-C by dephosphorylating ara-C monophosphate to ara-C. In this study, we sequenced NT5C2 in genomic DNA samples from International HapMap project panels with European [Centre d'Etude du Polymorphisme Humain (CEU); n = 90] or African [Yoruba people in Ibadan, Nigeria (YRI); n = 90] ancestry. We identified 41 genetic variants [one insertion-deletion and 40 single nucleotide polymorphisms (SNPs)], including three nonsynonymous SNPs (Y3A, K47R, and Q136R). Twenty-five SNPs were novel and 16 overlapped with the HapMap data. Subjects with African ancestry had NT5C2 mRNA expression levels that was significantly higher than those with European ancestry (p = 0.005). Furthermore, there was a correlation between NT5C2 mRNA expression and ara-C sensitivity in CEU but not in YRI cell lines. None of the nonsynonymous SNPs demonstrated any effect on NT5C2 activity. The genotypes of several SNPs were significantly associated with NT5C2 mRNA expression and/or ara-C sensitivity in CEU cell lines, but very few were significant in YRI cell lines. Of most interest, SNPs (linkage disequilibrium group CEU.12) in the 5′-untranslated region were associated with NT5C2 expression and ara-C sensitivity in HapMap cell lines and with NT5C2 mRNA expression and ara-C sensitivity in diagnostic leukemic blasts from pediatric patients with acute myeloid leukemia. Functional genomics analysis demonstrated that the promoter SNP rs11191612 was associated with altered luciferase activation in reporter assays and altered DNA-protein binding in gel shift assays. These results suggest that genetic variations in NT5C2 influence its expression and, potentially, cellular responses to nucleoside analogs.

UR - http://www.scopus.com/inward/record.url?scp=80053148504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053148504&partnerID=8YFLogxK

U2 - 10.1124/jpet.111.182873

DO - 10.1124/jpet.111.182873

M3 - Article

VL - 339

SP - 9

EP - 23

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -