Abstract
The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3Kγ reduced migration of CLL cells and cell lines. Expression of the PI3Kγ subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3Kγ subunits enhanced cell migration in response to SDF1α/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3Kγ functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3Kγ inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3Kγ has unique functions in malignant B cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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CD40 Ligand / metabolism
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Cell Adhesion / drug effects
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Cell Adhesion / genetics
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Chemokines / metabolism
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Chemotaxis / genetics
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
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Class I Phosphatidylinositol 3-Kinases / genetics
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Class I Phosphatidylinositol 3-Kinases / metabolism*
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Class Ib Phosphatidylinositol 3-Kinase / genetics
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Class Ib Phosphatidylinositol 3-Kinase / metabolism*
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Cytoskeleton / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Knockdown Techniques
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Humans
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Immunoglobulin Heavy Chains / genetics
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Interleukin-4 / metabolism
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Leukemia, B-Cell / genetics
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Leukemia, B-Cell / metabolism*
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Leukemia, B-Cell / pathology
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism*
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Lymphoma, B-Cell / pathology
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Mesenchymal Stem Cells / metabolism
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Mutation
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Phosphoinositide-3 Kinase Inhibitors
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Purines / pharmacology
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Quinazolinones / pharmacology
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ZAP-70 Protein-Tyrosine Kinase / metabolism
Substances
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Antineoplastic Agents
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Chemokines
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Immunoglobulin Heavy Chains
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Phosphoinositide-3 Kinase Inhibitors
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Purines
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Quinazolinones
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CD40 Ligand
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Interleukin-4
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Class I Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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PIK3CD protein, human
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PIK3CG protein, human
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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idelalisib