Leukemic challenge unmasks a requirement for PI3Kdelta 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 PI3Kdelta and therefore explored its impact on leukemia development. Using PI3Kdelta-deficient mice, we define a dual role of PI3Kdelta 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 PI3Kdelta-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kdelta accelerated leukemia progression in vivo. However, the absence of PI3Kdelta also affected NK cell-mediated tumor surveillance. PI3Kdelta-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 PI3Kdelta-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 PI3Kdelta. Other tumor models confirmed that PI3Kdelta-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kdelta 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 PI3Kdelta inhibitors as antileukemic agents in clinical trials.
Zebedin
Eva
E
Institute of Pharmacology, Medical University of Vienna MUW, Vienna, Austria.
Simma
Olivia
O
Schuster
Christian
C
Putz
Eva Maria
EM
Fajmann
Sabine
S
Warsch
Wolfgang
W
Eckelhart
Eva
E
Stoiber
Dagmar
D
Weisz
Eva
E
Schmid
Johannes A
JA
Pickl
Winfried F
WF
Baumgartner
Christian
C
Valent
Peter
P
Piekorz
Roland P
RP
Freissmuth
Michael
M
Sexl
Veronika
V
D000011:Abelson murine leukemia virus / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D058534:Class I Phosphatidylinositol 3-Kinases; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007157:Immunologic Surveillance / Q000235:genetics*; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007938:Leukemia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C421683:Pik3cd protein, mouse