Targeting PI3Kδ and PI3Kγ signalling disrupts human AML survival and bone marrow stromal cell mediated protection.

Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key survival pathways in acute myeloid leukaemia (AML). It generates phosphatidylinositol-3,4,5-triphosphate, which provides a membrane docking site for protein kinaseB activation. PI3K catalytic p110 subunits are divided into 4 isoforms; alpha, beta, delta and gamma. The PI3K delta isoform is always expressed in AML cells, whereas the frequency of PI3K gamma expression is highly variable. The functions of these individual catalytic enzymes have not been fully resolved in AML, therefore using the PI3K p110 delta and p110 gamma-targeted inhibitor IPI-145 (duvelisib) and specific p110 delta and p110 gamma shRNA, we analysed the role of these two p110 subunits in human AML blast survival. The results show that PI3K delta and PI3K gamma inhibition with IPI-145 has anti-proliferative activity in primary AML cells by inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145 inhibits both adhesion and migration of AML blasts to bone marrow stromal cells. Using shRNA targeted to the individual isoforms we demonstrated that p110 delta-knockdown had a more significant anti-proliferative effect on AML cells, whereas targeting p110 gamma-knockdown significantly inhibited AML migration. The results demonstrate that targeting both PI3K delta and PI3K gamma to inhibit AML-BMSC interactions provides a biologic rationale for the pre-clinical evaluation of IPI-145 in AML.