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The downregulation of asparagine synthetase expression can increase the sensitivity of cells resistant to L-asparaginase

Leukemia volume 20, pages 2199–2201 (2006)Cite this article

L-asparaginase is a critical component of the combination chemotherapy for childhood acute lymphoblastic leukemia. It has been demonstrated to suppress the growth of leukemic cells by hydrolyzing asparagine to aspartic acid and ammonia, and causing the rapid depletion of asparagine in plasma. As a non-essential amino acid, asparagine could be synthesized from aspartate and glutamine by asparagine synthetase (AsnS) and is incorporated into amino-acid sequences of proteins.1 Following administration of L-asparaginase, leukemic cells cannot compensate for the additional requirement of asparagine for their growth and development owing to the lack of sufficient AsnS activity.2 The exact molecular events that cause cell death following L-asparaginase treatment keeps unknown. However, suppression of protein synthesis is an obvious potential target and it had been documented that L-asparaginase exposure could initiate apoptosis of the cells.3 Aslanian et al.4 overexpressed the AsnS protein in the Molt-4 cells using a Moloney mouse retrovirus system and induced the L-asparaginase resistance phenotype in the parental cells. Hutson et al.5 demonstrated that the AsnS messsnger RNA (mRNA) level was in parallel to the AsnS protein level. Like the AsnS enzyme activity, the AsnS mRNA level was also correlated with the cellular resistance, which indicated that the AsnS mRNA level was an index of cells resistance to L-asparaginase. Therefore, our study is to investigate the possibility of reversing the L-asparaginase resistance and to further investigate the correlation of AsnS expression with L-asparaginase resistance by downregulating the AsnS mRNA level.

Our studies revealed that AsnS protein and its activity have been suppressed by specific interference of AsnS gene expression. Greco A et al.7 demonstrated that temperature-sensitive AsnS mutants, when exposed to nonpermissive temperature, could not proceed through the cell cycle. In consistent with this, the AsnS mRNA interference cells displayed increased G0/G1 phase accumulation. After treating with L-asparaginase, AsnS mRNA interference cells showed more significant proliferation inhibition and apoptosis than the mock interference cells. Therefore, our results demonstrated that the L-asparaginase resistance of K562 and Karpas299 cells could be reversed through specifically downregulating the AsnS mRNA expression and the AsnS expression might be a potential target for dealing with L-asparaginase resistant leukemia.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China, No. 30470740 and by Shanghai Leading Academic Discipline Project, Project Number: T0204. We thank Lisong Shen, Liheng Ma and Fanfan Chen for expert technical assistances. We also thank Yanxia Zhao, Yan Miao, Xiangliang Yuan, Shaohua Shen, Rune Xiang and Jiaoyang Cai for technical advice and helpful discussion. We specially thank Dr Chris Wood for careful reading of the paper.

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  1. B S Li, L J Gu and C Y Luo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology/Oncology, Shanghai Children's Medical Center, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    B S Li, L J Gu, C Y Luo, S H Shen, H Jiang, S H Shen, J Chen, H L Xue & J Y Tang

  2. Department of Pediatric Surgery, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    W S Li

  3. Laboratory Diagnostic Center, Shanghai Children's Medical Center, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    L M Jiang & B Zhang

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Correspondence to L J Gu.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Li, B., Gu, L., Luo, C. et al. The downregulation of asparagine synthetase expression can increase the sensitivity of cells resistant to L-asparaginase. Leukemia 20, 2199–2201 (2006). https://doi.org/10.1038/sj.leu.2404423

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