Distinct roles for phosphoinositide 3-kinases γ and δ in malignant B cell migration

Leukemia. 2018 Sep;32(9):1958-1969. doi: 10.1038/s41375-018-0012-5. Epub 2018 Jan 31.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • CD40 Ligand / metabolism
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Chemokines / metabolism
  • Chemotaxis / genetics
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism*
  • Cytoskeleton / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Interleukin-4 / metabolism
  • Leukemia, B-Cell / genetics
  • Leukemia, B-Cell / metabolism*
  • Leukemia, B-Cell / pathology
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism*
  • Lymphoma, B-Cell / pathology
  • Mesenchymal Stem Cells / metabolism
  • Mutation
  • Phosphoinositide-3 Kinase Inhibitors
  • Purines / pharmacology
  • Quinazolinones / pharmacology
  • ZAP-70 Protein-Tyrosine Kinase / metabolism


  • Antineoplastic Agents
  • Chemokines
  • Immunoglobulin Heavy Chains
  • Phosphoinositide-3 Kinase Inhibitors
  • Purines
  • Quinazolinones
  • CD40 Ligand
  • Interleukin-4
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CD protein, human
  • PIK3CG protein, human
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • idelalisib