title: Differential mechanisms of asparaginase resistance in B-type acute lymphoblastic leukemia and malignant natural killer cell lines.
abstract: Bacterial L-asparaginase (ASNase), hydrolyzing L-asparagine (Asn), is an important drug for treating patients with acute lymphoblastic leukaemia (ALL) and natural killer (NK) cell lymphoma. Although different native or pegylated ASNase-based chemotherapy are efficient, disease relapse is frequently observed, especially in adult patients. The neo-synthesis of Asn by asparagine synthetase (AsnS) following ASNase treatment, which involves the amino acid response and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways, is believed to be the basis of ASNase-resistance mechanisms. However, AsnS expression has not emerged as an accurate predictive factor for ASNase susceptibility. The aim of this study was to identify possible ASNase sensitivity/resistance-related genes or pathways using a new asparaginase, namely a pegylated r-crisantaspase, with a focus on classic Asn-compensatory responses and cell death under conditions of Asn/L-glutamine limitation. We show that, for B-ALL cell lines, changes in the expression of apoptosis-regulatory genes (especially NFκB-related genes) are associated with ASNase susceptibility. The response of malignant NK cell lines to ASNase may depend on Asn-compensatory mechanisms and other cellular processes such as cleavage of BCL2A1, a prosurvival member of the Bcl-2 protein family. These results suggest that according to cellular context, factors other than AsnS can influence ASNase susceptibility.
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Wei-Wen
authors: WW
authors: Chien
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Céline
authors: C
authors: Le Beux
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Nicolas
authors: N
authors: Rachinel
authors: Alizeé Pharma, 15 Chemin du Saquin, Espace Européen, Building G, 69130, Ecully, FRANCE.
authors: Michel
authors: M
authors: Julien
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Claire-Emmanuelle
authors: CE
authors: Lacroix
authors: Alizeé Pharma, 15 Chemin du Saquin, Espace Européen, Building G, 69130, Ecully, FRANCE.
authors: Soraya
authors: S
authors: Allas
authors: Alizeé Pharma, 15 Chemin du Saquin, Espace Européen, Building G, 69130, Ecully, FRANCE.
authors: Pierre
authors: P
authors: Sahakian
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Aurélie
authors: A
authors: Cornut-Thibaut
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Loïc
authors: L
authors: Lionnard
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Jérôme
authors: J
authors: Kucharczak
authors: Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE.
authors: Abdel
authors: A
authors: Aouacheria
authors: Alizeé Pharma, 15 Chemin du Saquin, Espace Européen, Building G, 69130, Ecully, FRANCE.
authors: Thierry
authors: T
authors: Abribat
authors: 1] Université Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE [2] Hospices Civils de Lyon, Service d'Hématologie, 165 Chemin du Grand Revoyet, 69495 Pierre-Bénite, FRANCE.
authors: Gilles
authors: G
authors: Salles
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001215:Asparaginase / Q000633:toxicity*; D001217:Aspartate-Ammonia Ligase / Q000633:toxicity; D045744:Cell Line, Tumor; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase
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