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 c... More
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.
