Distinct roles for phosphoinositide 3-kinases ? and ? in malignant B cell migration.

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 PI3K?-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3K? has not been extensively studied in B cells. Here, we assess whether PI3K? has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3K? inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3K?/? inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3K? reduced migration of CLL cells and cell lines. Expression of the PI3K? subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3K? subunits enhanced cell migration in response to SDF1?/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3K? functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3K? inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3K? has unique functions in malignant B cells.

SUBMITTER: Ali AY 

PROVIDER: S-EPMC6127087 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature