Leukemic challenge unmasks a requirement for PI3K delta in NK cell-mediated tumor surveillance

Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL(+) human leukemic cells express PI3K delta and therefore explored its impact on leukemia development. Using PI3K delta-deficient mice, we define a dual role of PI3K delta in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell-mediated tumor surveillance: Abelson-transformed PI3K delta-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3K delta accelerated leukemia progression in vivo. However, the absence of PI3K delta also affected NK cell-mediated tumor surveillance. PI3K delta-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3K delta-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3K delta. Other tumor models confirmed that PI3K delta-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3K delta in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3K delta inhibitors as antileukemic agents in clinical trials. ( Blood. 2008; 112: 4655-4664)