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; α,β,δ and γ. The PI3Kδ isoform is always expressed in AML cells, 
whereas the frequency of PI3Kγ expression is highly variable. The functions of 
these individual catalytic enzymes have not been fully resolved in AML, 
therefore using the PI3K p110δ and p110γ-targeted inhibitor IPI-145 (duvelisib) 
and specific p110δ and p110γ shRNA, we analysed the role of these two p110 
subunits in human AML blast survival. The results show that PI3Kδ and PI3Kγ 
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 
p110δ-knockdown had a more significant anti-proliferative effect on AML cells, 
whereas targeting p110γ-knockdown significantly inhibited AML migration. The 
results demonstrate that targeting both PI3Kδ and PI3Kγ to inhibit AML-BMSC 
interactions provides a biologic rationale for the pre-clinical evaluation of 
IPI-145 in AML.