A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85376
Title:
A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase.
Authors:
Patel, Naina; Krishnan, Shekhar; Offman, Marc N; Krol, Marcin; Moss, Catherine X; Leighton, Carly; Van Delft, Frederik W; Holland, Mark; Liu, Jizhong; Alexander, Seema; Dempsey, Clare E; Ariffin, Hany; Essink, Monika; Eden, Tim O B; Watts, Colin; Bates, Paul A; Saha, Vaskar
Abstract:
l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.
Affiliation:
Cancer Research UK Children's Cancer Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
Citation:
A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase. 2009, 119 (7):1964-73 J. Clin. Invest.
Journal:
The Journal of Clinical Investigation
Issue Date:
Jul-2009
URI:
http://hdl.handle.net/10541/85376
DOI:
10.1172/JCI37977
PubMed ID:
19509471
Type:
Article
Language:
en
ISSN:
1558-8238
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPatel, Nainaen
dc.contributor.authorKrishnan, Shekharen
dc.contributor.authorOffman, Marc Nen
dc.contributor.authorKrol, Marcinen
dc.contributor.authorMoss, Catherine Xen
dc.contributor.authorLeighton, Carlyen
dc.contributor.authorVan Delft, Frederik Wen
dc.contributor.authorHolland, Marken
dc.contributor.authorLiu, Jizhongen
dc.contributor.authorAlexander, Seemaen
dc.contributor.authorDempsey, Clare Een
dc.contributor.authorAriffin, Hanyen
dc.contributor.authorEssink, Monikaen
dc.contributor.authorEden, Tim O Ben
dc.contributor.authorWatts, Colinen
dc.contributor.authorBates, Paul Aen
dc.contributor.authorSaha, Vaskaren
dc.date.accessioned2009-11-05T10:21:30Z-
dc.date.available2009-11-05T10:21:30Z-
dc.date.issued2009-07-
dc.identifier.citationA dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase. 2009, 119 (7):1964-73 J. Clin. Invest.en
dc.identifier.issn1558-8238-
dc.identifier.pmid19509471-
dc.identifier.doi10.1172/JCI37977-
dc.identifier.urihttp://hdl.handle.net/10541/85376-
dc.description.abstractl-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.en
dc.language.isoenen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAsparaginase-
dc.subject.meshCathepsin B-
dc.subject.meshCell Line-
dc.subject.meshCysteine Endopeptidases-
dc.subject.meshHumans-
dc.subject.meshLymphocytes-
dc.subject.meshLysosomes-
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphoma-
dc.titleA dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Children's Cancer Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.en
dc.identifier.journalThe Journal of Clinical Investigationen

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