Childhood T-cell acute lymphoblastic leukemia (T-ALL) still remains a therapeutic challenge due to relapses which are resistant to further treatment. l-asparaginase (ASNase) is a key therapy component in pediatric T-ALL and lower sensitivity of leukemia cells to this drug negatively influences overall treatment efficacy and outcome. PTEN protein deletion and/or activation of the PI3K/Akt signaling pathway leading to altered cell growth and metabolism are emerging as a common feature in T-ALL. We herein investigated the relationship amongst PTEN deletion, ASNase sensitivity and glucose metabolism in T-ALL cells. First, we found significant differences in the sensitivity to ASNase amongst T-ALL cell lines. While cell lines more sensitive to ASNase were PTEN wild type (WT) and had no detectable level of phosphorylated Akt (P-Akt), cell lines less sensitive to ASNase were PTEN-null with high P-Akt levels. Pharmacological inhibition of Akt in the PTEN-null cells rendered them more sensitive to ASNase and lowered their glycolytic function which then resembled PTEN WT cells. In primary T-ALL cells, although P-Akt level was not dependent exclusively on PTEN expression, their sensitivity to ASNase could also be increased by pharmacological inhibition of Akt. In summary, we highlight a promising therapeutic option for T-ALL patients with aberrant PTEN/PI3K/Akt signaling.
Background:L-asparaginase (ASNase) is one of the crucial drugs used in treatment of childhood acute lymphoblastic leukemia (ALL). Leukemia cells are sensitive to ASNase because they have lower asparagine synthetase (ASNS) level compared to healthy cells and other tumors. However, correlations of ASNS gene expression or enzyme production with sensitivity of leukemia to ASNase are inconsistent. Notably, ASNase used in vitro depletes all asparagine (Asn) and glutamine (Gln) whereas it is probably only Asn that is completely depleted in vivo after ASNase administration in ALL treatment with unchanged or lowered Gln concentration.
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