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

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206 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 languageEnglish (US)
Pages (from-to)368-371
Number of pages4
JournalNature Medicine
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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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