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

Leukemia
Ahmed Y AliAaron James Marshall

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 adhes...Continue Reading

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Citations

May 9, 2019·Pharmaceuticals·Daniel A RodriguesCarlos A M Fraga
May 30, 2019·Future Oncology·Anna M FrustaciMarco Montillo
Sep 27, 2019·Blood·Krish PatelJohn M Pagel
Apr 16, 2020·Expert Opinion on Pharmacotherapy·Anna Maria FrustaciMarco Montillo
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Jan 24, 2019·International Journal of Molecular Sciences·Vanessa Edna SanchezYong-Mi Kim
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Dec 9, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Folayemi AdefemiAaron J Marshall
Jan 28, 2021·Expert Review of Anticancer Therapy·Liana NikolaenkoAlexey V Danilov
Jun 28, 2021·Hematology/oncology Clinics of North America·Shanmugapriya Thangavadivel, Jennifer A Woyach

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Datasets Mentioned

BETA
GDS4176

Methods Mentioned

BETA
transfection
flow cytometry

Software Mentioned

IMARIS

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