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Cited by 70Acute Lymphoblastic Leukemia researchAmino Acid Enzymes and MetabolismRetinoids in leukemia and cellular processes

Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia

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Appel, Inge M., den Boer, Monique L., Meijerink, Jules P. P., Veerman, Anjo J. P., Reniers, Nathalie C. M., Pieters, Rob·2006·Blood
DOI 10.1182/blood-2005-06-2597
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Abstract

l-asparaginase (l-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of l-Asp by resynthesis of asparagine. In vitro, resistance to l-Asp has been associated with up-regulation of AS mRNA expression. We monitored AS mRNA levels in leukemic cells before and during 5 days after intravenous administration of 1000 IU/m2 pegylated l-asparaginase (PEG-Asp) in a therapeutic window in children with ALL at initial diagnosis. Within 24 hours, AS mRNA levels increased by 3.5-fold and remained stable in the following 4 days. Baseline and l-Asp–induced expression levels of AS did not differ between clinically good, intermediate, and poor responders to PEG-Asp. No significant difference of AS mRNA up-regulation was found between precursor B- and T-ALL or between hyperdiploids, TEL/AML1 rearranged ALL or absence of genetic abnormalities. In 3 of 12 patients with T-ALL even a slight down-regulation of AS mRNA expression upon l-Asp exposure was found. In conclusion, although l-Asp exposure induces the expression of AS mRNA, the up-regulated gene expression does not correlate with an early clinical poor response to this drug in children with ALL.

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Crossref · 10.1182/blood-2005-06-2597

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  • Clinical response to L-asparaginase treatment is independent of asparagine synthase expression.

    “Though the mechanism of asparagine auxotrophy in ALL cells was assumed to be genetically defined, studies have shown that clinical response to L-asparaginase treatment is independent of asparagine synthase (ASNS) expression, the enzyme that converts aspartate to asparagine (Figure 7) (Appel et al., 2006; Stams et al., 2003).”

    From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Appel et al., 2006

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Authors
Appel, I. M., den Boer, M. L., Meijerink, J. P. P., Veerman, A. J. P., Reniers, N. C. M., & Pieters, R.
Affiliations
  • Erasmus MC (NL)
  • From the Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children`s Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands; and the Dutch Childhood Oncology Group, The Hague, The Netherlands.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2006-06-01
Volume
107
Issue
11
Pages
4244-4249
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2005-06-2597
OpenAlex
W2001161985
Cited by
70
References
37
Citations by year
2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 6
FWCI
4.67
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords
asparagine synthetase, L-asparaginase, childhood acute lymphoblastic leukemia, asparagine depletion, drug resistance, gene upregulation, clinical response, T-cell acute lymphoblastic leukemia, B-cell precursor acute lymphoblastic leukemia, hyperdiploidy
MeSH terms
Adolescent, Antineoplastic Agents, Asparaginase, Aspartate-Ammonia Ligase, Child, Child, Preschool, Female, Humans, Infant, Male, Polyethylene Glycols, RNA, Neoplasm, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Leukemia-Lymphoma, Adult T-Cell, Up-Regulation, Treatment Outcome, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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