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Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells

Leukemia volume 18, pages 434–441 (2004)Cite this article

Abstract

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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Acknowledgements

This work was supported by the Grant Agency of Charles University #57, Internal Grant Agency of Ministry of Health #7433, Ministry of Education: #111100004, #111300003, #111300001; JS was supported by Ministry of Education FRVS #1011 and work of OH by Ministry of Health #00000064203. The collaboration of all Czech Paediatric Haematology (CPH) centres (leaders: B Blazek (Ostrava), Z Cerna (Plzen), Y Jabali (Ceske Budejovice), V Mihal (Olomouc), D Prochazkova (Usti nad Labem), J Stary (Praha), J Sterba (Brno), K Tousovska (Hradec Kralove)) is highly appreciated.

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  1. O Krejci and J Starkova: Both authors contributed equally to this work

Authors and Affiliations

  1. CLIP – Childhood Leukaemia Investigation Prague, Prague, Czech Republic

    O Krejci, J Starkova, J Madzo, M Kalinova, O Hrusak & J Trka

  2. 2nd Department of Paediatrics, Charles University 2nd Medical School, Prague, Czech Republic

    O Krejci, J Starkova, J Madzo, M Kalinova & J Trka

  3. Institute of Biology and Department of Medical Genetics, Charles University 1st Medical School, Prague, Czech Republic

    B Otova

  4. Institute of Immunology, Charles University 2nd Medical School, Prague, Czech Republic

    O Hrusak

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  1. O Krejci
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Correspondence to O Krejci.

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Krejci, O., Starkova, J., Otova, B. et al. Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells. Leukemia 18, 434–441 (2004). https://doi.org/10.1038/sj.leu.2403259

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