Dataset: Gene expression signature of T-ALL cell lines treated with the PI3K inhibitor AS605240

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K effector mTOR has been suggested to represent one mechanism of glucocorticoids resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, a PI3K gene expression signature allowed us to infer that higher PI3K activity is associated with glucocorticoid resistance and worst clinical outcome in T-ALL. The PI3K inhibitor AS605240 showed anti-leukemic activity and prevented leukemic progression in a xenograft model of T-ALL in NOD/SCID mice. Moreover, treatment of T-ALL cells with AS605240 downregulated Myc protein levels and Myc-dependent transcription in a Notch1-independent manner. Our data indicate that PI3K and Notch1 pathway converge at Myc, which was previously associated with glucocorticoids resistance in T-ALL. Accordingly, AS605240 showed strong synergism with glucocorticoids both in vitro and in T-ALL xenografted NOD/SCID mice. Surprisingly, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction could be circumvented by the use of correct drug scheduling schemes, which may be of major importance when considering introducing PI3K inhibitors in T-ALL treatment schemes. T-ALL cell lines were treated with the PI3K inhibitor AS605240 or vehicle for 6h in order to define a gene expression signature characteristic of PI3K activity in T-ALL cells. Seven T-ALL cell lines (CCRF-CEM, HPB-ALL, Molt-4, ALL-SIL, P12-ICHIKAWA, TALL-1 and Jurkat) were cultured for 6h with the respective IC50 concentration of AS605240 or vehicle.

Species:

human

Samples:

14

Source:

E-GEOD-50998

Updated:

Dec.12, 2014

Registered:

Sep.21, 2014