Immuno-oncology

Poster

pi3kγ Signaling Enhances Microenvironmental Interaction and Survival of Chronic Lymphocytic Leukemia Cells

Wednesday, June 14
6:15 PM - 7:45 PM

CLL is the most prevalent hematologic malignancy among adults and remains incurable. CLL cells rely on BCR signaling for their survival. Interactions with stromal cells within the microenvironment are critical for CLL survival and disease progression by protecting them from chemotherapeutics. Blocking these interactions represents an important therapeutic strategy. PI3K enzymes have essential roles in signal transduction via the BCR, and Idelalisib (PI3Kδ-specific inhibitor) shows efficacy in CLL treatment. PI3Kγ has been extensively studied in T cell receptor signaling, but not in B cells. However, PI3Kγ inhibitors are now in clinical development for B cell malignancies. Here we assess whether PI3Kγ is a critical factor controlling CLL migration and retention in the microenvironment. We observed that expression of p110γ catalytic subunit and p101 adaptor subunit increased in CLL cells in response to CD40L+IL-4 stimulation but not BCR cross-linking. The adaptor subunit p84 was minimally expressed in CLL cells. PI3Kγ inhibition reduced CLL cell migration and adhesion to stromal cells. CRISPR-mediated knockdown of p110γ caused a reduction in migration of CLL cells and cell lines, while overexpression of p110γ significantly enhanced ZAP70+ CLL cell migration. PI3Kγ inhibition impaired cell migration to a similar extent as Idelalisib or the dual PI3Kδ/γ inhibitor Duvelisib.  Microscopic examination of cell migration behavior within SDF1α gradients revealed that PI3Kγ has an important role in chemokine gradient sensing and impacts on cell polarization induced upon chemokine exposure.  Together our findings provide evidence that PI3Kγ has unique and important functions in chemokine-dependent responses in B cells.

Ahmed YASSEN. Ali

Postdoctoral Fellow
University of Manitoba, Dept of Immunology

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    Aaron Marshall

    University of Manitoba/Dept. of Immunology

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      Spencer B. Gibson

      Senior Investigator
      Research Institute in Oncology and Hematology

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