Cited by 103Acute Lymphoblastic Leukemia researchAmino Acid Enzymes and MetabolismBiochemical and Molecular Research

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A Genome-Wide View of the In vitro Response to l-Asparaginase in Acute Lymphoblastic Leukemia

Fine, Bernard M., Kaspers, Gertjan J.L., Ho, Minh, Loonen, Anne H., Boxer, Linda M.·2005·Cancer Research

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Abstract

To investigate the effect of l-asparaginase on acute lymphoblastic leukemia (ALL), we used cDNA microarrays to obtain a genome-wide view of gene expression both at baseline and after in vitro exposure to l-asparaginase in cell lines and pediatric ALL samples. In 16 cell lines, a baseline gene expression pattern distinguished l-asparaginase sensitivity from resistance. However, for 28 pediatric ALL samples, no consistent baseline expression pattern was associated with sensitivity to l-asparaginase. In particular, baseline expression of asparagine synthetase (ASNS) was not predictive of response to l-asparaginase. After exposure to l-asparaginase, 5 cell lines and 10 clinical samples exhibited very similar changes in the expression of a large number of genes. However, the gene expression changes occurred more slowly in the clinical samples. These changes included a consistent increase in expression of tRNA synthetases and solute transporters and activating transcription factor and CCAAT/enhancer binding protein family members, a response similar to that observed with amino acid starvation. There was also a consistent decrease in many genes associated with proliferation. Taken together, the changes seem to reflect a consistent coordinated response to asparagine starvation in both cell lines and clinical samples. Importantly, in the clinical samples, increased expression of ASNS after l-asparaginase exposure was not associated with in vitro resistance to l-asparaginase, indicating that ASNS-independent mechanisms of in vitro l-asparaginase resistance are common in ALL. These results suggest that targeting particular genes involved in the response to amino acid starvation in ALL cells may provide a novel way to overcome l-asparaginase resistance.

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Authors: Fine, B. M., Kaspers, G. J. L., Ho, M., Loonen, A. H., & Boxer, L. M.
Affiliations: Howard Hughes Medical Institute (US)
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
VA Palo Alto Health Care System (US)
ORCID: Fine, Bernard M.
Kaspers, Gertjan J.L.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2005-01-01
Volume: 65
Issue: 1
Pages: 291-299
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.291.65.1
OpenAlex: W1867192423
Cited by: 103
References: 52
Citations by year: 2025: 3 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 8 · 2014: 11 · 2012: 5
FWCI: 10.44
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: National Institutes of Health (1r01ca092326-01)
National Cancer Institute (CA85129, CA92326, K08CA095563, U01CA085129)
Topics: Health Sciences › Medicine › Hematology › 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 › Biochemical and Molecular Research
Keywords: L-asparaginase, acute lymphoblastic leukemia, pediatric leukemia, gene expression profiling, asparagine synthetase, drug resistance, tRNA synthetase, amino acid transporters, C/EBP transcription factors, cell proliferation, leukemia cell lines
MeSH terms: Adolescent, Antineoplastic Agents, Asparaginase, Child, Female, Humans, Male, Recurrence, Translocation, Genetic, Genome, Human, Artificial Gene Fusion, Cell Line, Tumor, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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A Genome-Wide View of the In vitro Response to l-Asparaginase in Acute Lymphoblastic Leukemia

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