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

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

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemother...

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Main Authors: Tzoneva, Gannie, Garcia, Arianne Perez, Carpenter, Zachary, Khiabanian, Hossein, Tosello, Valeria, Allegretta, Maddalena, Paietta, Elisabeth, Racevskis, Janis, Rowe, Jacob M., Tallman, Martin S., Paganin, Maddalena, Basso, Giuseppe, Hof, Jana, Kirschner-Schwabe, Renate, Palomero, Teresa, Rabadan, Raul, Ferrando, Adolfo
Format: Online
Language:English
Published: 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594483/
id pubmed-3594483
recordtype oai_dc
spelling pubmed-35944832013-09-01 Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL Tzoneva, Gannie Garcia, Arianne Perez Carpenter, Zachary Khiabanian, Hossein Tosello, Valeria Allegretta, Maddalena Paietta, Elisabeth Racevskis, Janis Rowe, Jacob M. Tallman, Martin S. Paganin, Maddalena Basso, Giuseppe Hof, Jana Kirschner-Schwabe, Renate Palomero, Teresa Rabadan, Raul Ferrando, Adolfo Article Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease1,2. Using whole exome sequencing, here we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. 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. 2013-02-03 2013-03 /pmc/articles/PMC3594483/ /pubmed/23377281 http://dx.doi.org/10.1038/nm.3078 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Tzoneva, Gannie
Garcia, Arianne Perez
Carpenter, Zachary
Khiabanian, Hossein
Tosello, Valeria
Allegretta, Maddalena
Paietta, Elisabeth
Racevskis, Janis
Rowe, Jacob M.
Tallman, Martin S.
Paganin, Maddalena
Basso, Giuseppe
Hof, Jana
Kirschner-Schwabe, Renate
Palomero, Teresa
Rabadan, Raul
Ferrando, Adolfo
spellingShingle Tzoneva, Gannie
Garcia, Arianne Perez
Carpenter, Zachary
Khiabanian, Hossein
Tosello, Valeria
Allegretta, Maddalena
Paietta, Elisabeth
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
author_facet Tzoneva, Gannie
Garcia, Arianne Perez
Carpenter, Zachary
Khiabanian, Hossein
Tosello, Valeria
Allegretta, Maddalena
Paietta, Elisabeth
Racevskis, Janis
Rowe, Jacob M.
Tallman, Martin S.
Paganin, Maddalena
Basso, Giuseppe
Hof, Jana
Kirschner-Schwabe, Renate
Palomero, Teresa
Rabadan, Raul
Ferrando, Adolfo
author_sort Tzoneva, Gannie
title Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
title_short Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
title_full Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
title_fullStr Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
title_full_unstemmed Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
title_sort activating mutations in the nt5c2 nucleotidase gene drive chemotherapy resistance in relapsed all
description Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease1,2. Using whole exome sequencing, here we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. 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.
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594483/
_version_ 1611961339563999232

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