Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Gannie Tzoneva, Arianne Perez-Garcia, Zachary Carpenter, Hossein Khiabanian, Valeria Tosello, Maddalena Allegretta, Elisabeth M. Paietta, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Maddalena Paganin, Giuseppe Basso, Jana Hof, Renate Kirschner-Schwabe, Teresa Palomero, Raul Rabadan, Adolfo Ferrando

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5′-nucleotidase II gene (NT5C2), which encodes a 5′-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

Original languageEnglish (US)
Pages (from-to)368-371
Number of pages4
JournalNature Medicine
Volume19
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

nucleotidase
Chemotherapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genes
Drug Therapy
Mutation
Recurrence
5'-Nucleotidase
Nucleosides
Exome
Thioguanine
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
6-Mercaptopurine
Pediatrics
Disease Resistance
T-cells
Mutant Proteins
Metabolism
Disease Progression
Tumors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tzoneva, G., Perez-Garcia, A., Carpenter, Z., Khiabanian, H., Tosello, V., Allegretta, M., ... Ferrando, A. (2013). Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nature Medicine, 19(3), 368-371. https://doi.org/10.1038/nm.3078

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. / Tzoneva, Gannie; Perez-Garcia, Arianne; Carpenter, Zachary; Khiabanian, Hossein; Tosello, Valeria; Allegretta, Maddalena; Paietta, Elisabeth M.; Racevskis, Janis; Rowe, Jacob M.; Tallman, Martin S.; Paganin, Maddalena; Basso, Giuseppe; Hof, Jana; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo.

In: Nature Medicine, Vol. 19, No. 3, 03.2013, p. 368-371.

Research output: Contribution to journalArticle

Tzoneva, G, Perez-Garcia, A, Carpenter, Z, Khiabanian, H, Tosello, V, Allegretta, M, Paietta, EM, Racevskis, J, Rowe, JM, Tallman, MS, Paganin, M, Basso, G, Hof, J, Kirschner-Schwabe, R, Palomero, T, Rabadan, R & Ferrando, A 2013, 'Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL', Nature Medicine, vol. 19, no. 3, pp. 368-371. https://doi.org/10.1038/nm.3078
Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nature Medicine. 2013 Mar;19(3):368-371. https://doi.org/10.1038/nm.3078
Tzoneva, Gannie ; Perez-Garcia, Arianne ; Carpenter, Zachary ; Khiabanian, Hossein ; Tosello, Valeria ; Allegretta, Maddalena ; Paietta, Elisabeth M. ; Racevskis, Janis ; Rowe, Jacob M. ; Tallman, Martin S. ; Paganin, Maddalena ; Basso, Giuseppe ; Hof, Jana ; Kirschner-Schwabe, Renate ; Palomero, Teresa ; Rabadan, Raul ; Ferrando, Adolfo. / Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. In: Nature Medicine. 2013 ; Vol. 19, No. 3. pp. 368-371.
@article{9828c5a368cd491ba2e268463037986b,
title = "Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL",
abstract = "Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20{\%} of pediatric patients and over 50{\%} of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5′-nucleotidase II gene (NT5C2), which encodes a 5′-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19{\%}) relapse T cell ALLs and 1/35 (3{\%}) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.",
author = "Gannie Tzoneva and Arianne Perez-Garcia and Zachary Carpenter and Hossein Khiabanian and Valeria Tosello and Maddalena Allegretta and Paietta, {Elisabeth M.} and Janis Racevskis and Rowe, {Jacob M.} and Tallman, {Martin S.} and Maddalena Paganin and Giuseppe Basso and Jana Hof and Renate Kirschner-Schwabe and Teresa Palomero and Raul Rabadan and Adolfo Ferrando",
year = "2013",
month = "3",
doi = "10.1038/nm.3078",
language = "English (US)",
volume = "19",
pages = "368--371",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

AU - Tzoneva, Gannie

AU - Perez-Garcia, Arianne

AU - Carpenter, Zachary

AU - Khiabanian, Hossein

AU - Tosello, Valeria

AU - Allegretta, Maddalena

AU - Paietta, Elisabeth M.

AU - Racevskis, Janis

AU - Rowe, Jacob M.

AU - Tallman, Martin S.

AU - Paganin, Maddalena

AU - Basso, Giuseppe

AU - Hof, Jana

AU - Kirschner-Schwabe, Renate

AU - Palomero, Teresa

AU - Rabadan, Raul

AU - Ferrando, Adolfo

PY - 2013/3

Y1 - 2013/3

N2 - Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5′-nucleotidase II gene (NT5C2), which encodes a 5′-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

AB - Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5′-nucleotidase II gene (NT5C2), which encodes a 5′-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

UR - http://www.scopus.com/inward/record.url?scp=84875158235&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875158235&partnerID=8YFLogxK

U2 - 10.1038/nm.3078

DO - 10.1038/nm.3078

M3 - Article

C2 - 23377281

AN - SCOPUS:84875158235

VL - 19

SP - 368

EP - 371

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 3

ER -