Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells
Language English Country Great Britain, England Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
14724653
DOI
10.1038/sj.leu.2403259
PII: 2403259
Knihovny.cz E-resources
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma enzymology genetics pathology MeSH
- Asparaginase therapeutic use MeSH
- Aspartate-Ammonia Ligase metabolism MeSH
- Cell Cycle * MeSH
- Child MeSH
- Oncogene Proteins, Fusion metabolism MeSH
- Bone Marrow MeSH
- Humans MeSH
- Neoplasm Recurrence, Local metabolism pathology MeSH
- RNA, Messenger genetics MeSH
- Tumor Cells, Cultured MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Child, Preschool MeSH
- Core Binding Factor Alpha 2 Subunit MeSH
- RNA, Neoplasm genetics MeSH
- Up-Regulation MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Asparaginase MeSH
- Aspartate-Ammonia Ligase MeSH
- Oncogene Proteins, Fusion MeSH
- RNA, Messenger MeSH
- Core Binding Factor Alpha 2 Subunit MeSH
- RNA, Neoplasm MeSH
- TEL-AML1 fusion protein MeSH Browser
L-Asparaginase is a standard component in chemotherapy of childhood acute lymphoblastic leukaemia (ALL). Leukaemic cells carrying TEL/AML1 fusion gene are more sensitive to treatment with L-asparaginase compared to other subtypes of ALL. We demonstrate in vitro the prolonged growth suppression of TEL/AML1[+] cells compared to TEL/AML1[-] leukaemic cells after L-asparaginase treatment simulating treatment protocol. Cell cycle analysis revealed TEL/AML1[+] cells to accumulate in G1/G0 phase (81-98%) compared to TEL/AML1[-] cells (47-60%). Quantitative analysis of asparagine synthetase (AsnS) expression showed the ability of TEL/AML1[+] cells to increase AsnS mRNA levels after L-asparaginase treatment to the same extent as TEL/AML1[-] leukaemic and nonleukaemic lymphoid cells. We hypothesise that TEL/AML1[+] cells are unable to progress into the S phase of cell cycle under nutrition stress caused by L-asparaginase, despite the ability of AsnS upregulation. Significantly higher expression of AsnS was found in untreated leukaemic cells from children with TEL/AML1[+] ALL (n=20) in comparison with the group of age-matched children with ALL bearing no known fusion gene (n=25; P=0.0043). Interestingly, none of the TEL/AML1[+] patients with high AsnS level relapsed, whereas 10/15 patients with AsnS below median relapsed (P=0.00028). Therefore, high AsnS levels in TEL/AML1[+] patients correlate with better prognosis, possibly reflecting the stretched metabolic demand of the lymphoblast.
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