Abstract
The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer [1]
Using paired Limma analysis, we obtained 211 genes downregulated and 78 genes upregulated in T-ALL primary cells and 174 genes downregulated and 395 genes upregulated in T-ALL cell lines in response to AS605240 treatment
Connectivity Map analysis showed that the signature resulting from PI3K inhibition in T-ALL cell lines correlated with signatures of classical PI3K inhibitors, and rapamycin
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer [1]. The prognosis of children with T-ALL has improved with modern treatment protocols, based on the use of aggressive multiagent therapies [2]. T-ALL patients displaying chemotherapy resistance show very poor survival. Accumulating evidence indicates that the PI3K pathway is linked to resistance to therapy in several types of cancer [3]. Class I PI3Ks are a family of lipid kinases predominantly activated by protein tyrosine kinases in response to cell surface receptors. PI3K phosphorylates phosphatidylinositol 4, 5-bisphosphate (PIP2) generating phosphatidylinositol 3, 4, 5-trisphosphate (PIP3). PIP3 serves as an anchor for pleckstrin homology (PH)
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