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 Paietta; Janis Racevskis; Jacob M. Rowe; Martin S. Tallman; Maddalena Paganin; Giuseppe Basso; Jana Hof; Renate Kirschner-Schwabe; Teresa Palomero; Raul Rabadan; Adolfo Ferrando

doi:10.1038/nm.3078

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 Paietta, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Maddalena Paganin, Giuseppe Basso, Jana Hof, Renate Kirschner-Schwabe, Teresa Palomero^*, Raul Rabadan, Adolfo Ferrando

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

297 Scopus citations

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 language	English (US)
Pages (from-to)	368-371
Number of pages	4
Journal	Nature Medicine
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/nm.3078
State	Published - Mar 2013

Funding

We thank A.A. Da Silva for technical support in the production of recombinant NT5C2 proteins and R. Parsons for insightful comments and advice. We also thank P.H. Wiernik as the Eastern Cooperative Oncology Group (ECOG) leukemia committee chair at the time the E2993 study was initiated. This work was supported by the St. Baldrick’s Foundation (A.F.), the Partnership for Cure Foundation (R.R.), the Innovative Research Award by the Stand Up to Cancer Foundation (A.F.), the Chemotherapy Foundation (A.F.), the Leukemia and Lymphoma Society Scholar Award (A.F.), the German Federal Ministry for Education and Research in the National Genome Research Network (grant 01GS0870 to R.K.-S.), the German Foundation for Childhood Cancer (grants DKS 2003.08 and 2007.02 to R.K.-S.), the US National Institutes of Health (U24 CA114737 to E.P.) and the ECOG Leukemia Tissue Bank. A.P.-G. is a postdoctoral researcher funded by the Rally Foundation.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.3078

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Tzoneva, G., Perez-Garcia, A., Carpenter, Z., Khiabanian, H., Tosello, V., Allegretta, M., Paietta, E., Racevskis, J., Rowe, J. M., Tallman, M. S., 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, 19(3), 368-371. https://doi.org/10.1038/nm.3078

@article{bd793b66e3194778b0a015df36c86c25,

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 Elisabeth Paietta 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",

note = "Funding Information: We thank A.A. Da Silva for technical support in the production of recombinant NT5C2 proteins and R. Parsons for insightful comments and advice. We also thank P.H. Wiernik as the Eastern Cooperative Oncology Group (ECOG) leukemia committee chair at the time the E2993 study was initiated. This work was supported by the St. Baldrick{\textquoteright}s Foundation (A.F.), the Partnership for Cure Foundation (R.R.), the Innovative Research Award by the Stand Up to Cancer Foundation (A.F.), the Chemotherapy Foundation (A.F.), the Leukemia and Lymphoma Society Scholar Award (A.F.), the German Federal Ministry for Education and Research in the National Genome Research Network (grant 01GS0870 to R.K.-S.), the German Foundation for Childhood Cancer (grants DKS 2003.08 and 2007.02 to R.K.-S.), the US National Institutes of Health (U24 CA114737 to E.P.) and the ECOG Leukemia Tissue Bank. A.P.-G. is a postdoctoral researcher funded by the Rally Foundation.",

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doi = "10.1038/nm.3078",

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Tzoneva, G, Perez-Garcia, A, Carpenter, Z, Khiabanian, H, Tosello, V, Allegretta, M, Paietta, E, 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

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

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

N1 - Funding Information: We thank A.A. Da Silva for technical support in the production of recombinant NT5C2 proteins and R. Parsons for insightful comments and advice. We also thank P.H. Wiernik as the Eastern Cooperative Oncology Group (ECOG) leukemia committee chair at the time the E2993 study was initiated. This work was supported by the St. Baldrick’s Foundation (A.F.), the Partnership for Cure Foundation (R.R.), the Innovative Research Award by the Stand Up to Cancer Foundation (A.F.), the Chemotherapy Foundation (A.F.), the Leukemia and Lymphoma Society Scholar Award (A.F.), the German Federal Ministry for Education and Research in the National Genome Research Network (grant 01GS0870 to R.K.-S.), the German Foundation for Childhood Cancer (grants DKS 2003.08 and 2007.02 to R.K.-S.), the US National Institutes of Health (U24 CA114737 to E.P.) and the ECOG Leukemia Tissue Bank. A.P.-G. is a postdoctoral researcher funded by the Rally Foundation.

PY - 2013/3

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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.

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ER -

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

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