Leukemic challenge unmasks a requirement for PI3Kδ in NK cell–mediated tumor surveillance

• Published in: Blood Vol. 112; no. 12; pp. 4655 - 4664
• Main Authors: Zebedin, Eva, Simma, Olivia, Schuster, Christian, Putz, Eva Maria, Fajmann, Sabine, Warsch, Wolfgang, Eckelhart, Eva, Stoiber, Dagmar, Weisz, Eva, Schmid, Johannes A., Pickl, Winfried F., Baumgartner, Christian, Valent, Peter, Piekorz, Roland P., Freissmuth, Michael, Sexl, Veronika
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.12.2008; Americain Society of Hematology
• Subjects: Biological and medical sciences; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Natural killer cell; Hematology; Surveillance; Leukemia; Malignant hemopathy; Tumor cell; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-02-139105

Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL+ human leukemic cells express PI3Kδ and therefore explored its impact on leukemia development. Using PI3Kδ-deficient mice, we define a dual role of PI3Kδ 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 PI3Kδ-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kδ accelerated leukemia progression in vivo. However, the absence of PI3Kδ also affected NK cell–mediated tumor surveillance. PI3Kδ-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 PI3Kδ-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 PI3Kδ. Other tumor models confirmed that PI3Kδ-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kδ 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 PI3Kδ inhibitors as antileukemic agents in clinical trials.