title: Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway.
abstract: CLL cell survival and proliferation is enhanced through direct contact with supporting cells present in lymphoid tissues. PI3Ks are critical signal transduction enzymes controlling B cell survival and activation. PI3K inhibitors have entered clinical trials and show promising therapeutic activity; however, it is unclear whether PI3K inhibitor drugs differentially affect ZAP-70 positive versus negative CLL cells or target specific microenvironmental interactions. Here we provide evidence that CD40L+IL-4, IL-8 or IL-6 enhance adhesion to stromal cells, with IL-6 showing a selective effect on ZAP-70 positive cells. Stimulatory effects of IL-8 or IL-6 are fully reversed by PI3K inhibition, while the effects of CD40L+IL-4 are partially reversed. While CD40L+IL-4 is the only stimulation increasing CLL cell survival for all patient groups, IL-6 protects ZAP-70 positive cells from cell death induced by PI3K inhibition. Altogether, our results indicate that targeting the PI3K pathway can reverse protective CLL-microenvironment interactions in both ZAP-70 positive and negative CLL despite their differences in cytokine responsiveness.
authors: University of Manitoba, Department of Immunology, Winnipeg, MB, Canada; Cancercare Manitoba, Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
authors: Sandrine T
authors: ST
authors: Lafarge
authors: Cancercare Manitoba, Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
authors: James B
authors: JB
authors: Johnston
authors: University of Manitoba, Department of Immunology, Winnipeg, MB, Canada; Cancercare Manitoba, Manitoba Institute of Cell Biology, Winnipeg, MB, Canada; University of Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, MB, Canada.
authors: Spencer B
authors: SB
authors: Gibson
authors: University of Manitoba, Department of Immunology, Winnipeg, MB, Canada; University of Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, MB, Canada. Electronic address: marshall@ms.umanitoba.ca.
authors: Aaron J
authors: AJ
authors: Marshall
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D005434:Flow Cytometry; D005663:Furans / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D023201:CD40 Ligand; D016207:Cytokines; D005663:Furans; D015847:Interleukin-4; D015850:Interleukin-6; D016209:Interleukin-8; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D051746:ZAP-70 Protein-Tyrosine Kinase; C522973:PI103
keywords: CD40L; CLL; IL-4; IL-6; IL-8; Microenvironment; PI3K pathway; ZAP-70