PMID- 25626693 OWN - NLM STAT- MEDLINE DCOM- 20160219 LR - 20211203 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 5 DP - 2015 Jan 28 TI - Differential mechanisms of asparaginase resistance in B-type acute lymphoblastic leukemia and malignant natural killer cell lines. PG - 8068 LID - 10.1038/srep08068 [doi] LID - 8068 AB - 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 NFkappaB-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. FAU - Chien, Wei-Wen AU - Chien WW AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Le Beux, Celine AU - Le Beux C AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Rachinel, Nicolas AU - Rachinel N AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Julien, Michel AU - Julien M AD - Alizee Pharma, 15 Chemin du Saquin, Espace Europeen, Building G, 69130, Ecully, FRANCE. FAU - Lacroix, Claire-Emmanuelle AU - Lacroix CE AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Allas, Soraya AU - Allas S AD - Alizee Pharma, 15 Chemin du Saquin, Espace Europeen, Building G, 69130, Ecully, FRANCE. FAU - Sahakian, Pierre AU - Sahakian P AD - Alizee Pharma, 15 Chemin du Saquin, Espace Europeen, Building G, 69130, Ecully, FRANCE. FAU - Cornut-Thibaut, Aurelie AU - Cornut-Thibaut A AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Lionnard, Loic AU - Lionnard L AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Kucharczak, Jerome AU - Kucharczak J AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Aouacheria, Abdel AU - Aouacheria A AD - Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE. FAU - Abribat, Thierry AU - Abribat T AD - Alizee Pharma, 15 Chemin du Saquin, Espace Europeen, Building G, 69130, Ecully, FRANCE. FAU - Salles, Gilles AU - Salles G AD - 1] Universite Claude Bernard Lyon 1, UMR 5239 CNRS ENS HCL, Faculte de Medecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921, BP12, Oullins, FRANCE [2] Hospices Civils de Lyon, Service d'Hematologie, 165 Chemin du Grand Revoyet, 69495 Pierre-Benite, FRANCE. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150128 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Multiprotein Complexes) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (eIF-2 Kinase) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.5.1.1 (Asparaginase) RN - EC 6.3.1.1 (Aspartate-Ammonia Ligase) SB - IM MH - Apoptosis/*drug effects MH - Apoptosis Regulatory Proteins/genetics/metabolism MH - Asparaginase/*toxicity MH - Aspartate-Ammonia Ligase/toxicity MH - Cell Line, Tumor MH - Humans MH - Killer Cells, Natural/cytology/drug effects/metabolism MH - Lymphoma/metabolism/pathology MH - Mechanistic Target of Rapamycin Complex 1 MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Multiprotein Complexes/metabolism MH - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/metabolism MH - eIF-2 Kinase/metabolism PMC - PMC5389037 COIS- S.A. P.S., M.J. and T.A. are employees, and T.A. is a shareholder of Alize Pharma II. Alize Pharma II owns patent rights to pegylated r-crisantaspase. The remaining authors declare no competing financial interests. EDAT- 2015/01/30 06:00 MHDA- 2016/02/20 06:00 PMCR- 2015/01/28 CRDT- 2015/01/29 06:00 PHST- 2014/10/08 00:00 [received] PHST- 2015/01/02 00:00 [accepted] PHST- 2015/01/29 06:00 [entrez] PHST- 2015/01/30 06:00 [pubmed] PHST- 2016/02/20 06:00 [medline] PHST- 2015/01/28 00:00 [pmc-release] AID - srep08068 [pii] AID - 10.1038/srep08068 [doi] PST - epublish SO - Sci Rep. 2015 Jan 28;5:8068. doi: 10.1038/srep08068.