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.
authors: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors: Gannie
authors: G
authors: Tzoneva
authors: Arianne
authors: A
authors: Perez-Garcia
authors: Zachary
authors: Z
authors: Carpenter
authors: Hossein
authors: H
authors: Khiabanian
authors: Valeria
authors: V
authors: Tosello
authors: Maddalena
authors: M
authors: Allegretta
authors: Elisabeth
authors: E
authors: Paietta
authors: Janis
authors: J
authors: Racevskis
authors: Jacob M
authors: JM
authors: Rowe
authors: Martin S
authors: MS
authors: Tallman
authors: Maddalena
authors: M
authors: Paganin
authors: Giuseppe
authors: G
authors: Basso
authors: Jana
authors: J
authors: Hof
authors: Renate
authors: R
authors: Kirschner-Schwabe
authors: Teresa
authors: T
authors: Palomero
authors: Raul
authors: R
authors: Rabadan
authors: Adolfo
authors: A
authors: Ferrando
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D015122:Mercaptopurine / Q000627:therapeutic use*; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D017422:Sequence Analysis, DNA; D013866:Thioguanine / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001087:Arabinonucleosides; C104457:nelarabine; D015122:Mercaptopurine; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human; D013866:Thioguanine
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