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