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
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.
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U2 - 10.1038/nm.3078
DO - 10.1038/nm.3078
M3 - Article
C2 - 23377281
AN - SCOPUS:84875158235
SN - 1078-8956
VL - 19
SP - 368
EP - 371
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -