Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia

Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia

Bibliographic Details
Main Author: Dong, Shuai
Language:English
Published: The Ohio State University / OhioLINK 2017
Subjects:
Biomedical Research
Pharmaceuticals
Immunology
Chronic lymphocytic leukemia
PI3K p110delta
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1503066319794882
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15030663197948822021-08-03T07:03:57Z Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia Dong, Shuai Biomedical Research Pharmaceuticals Immunology Chronic lymphocytic leukemia PI3K p110delta Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western world. The treatment strategies of CLL have undergone a paradigm shift in the last decade. Without a disease defining gene abnormality, the Achilleas heels of CLL is its microenvironment dependency. Upon discovering the importance of CLL-microenvironment cross-talk and essential survival B cell receptor (BCR) pathways, small molecule inhibitors that target BCR pathways were soon developed and showed profound activity in preclinical and clinical studies. Several agents that target BCR pathways also reverse tumor related immune suppression. Idelalisib is one such therapy directed at phosphoinositide 3-kinase isoform d, an essential component of BCR signaling in normal and transformed B-cells and essential for the activation of regulatory T cells. CLL is dependent upon BCR signaling and mediates profound immune suppression and tumor tolerance. Idelalisib is a PI3K p110d inhibitor with significant clinical benefit and also toxicities resembling autoimmunity. Using a PI3K p110delta and p110gamma inhibitor IPI-145, we show that PI3K p110delta/p110gamma blockade in leukemia cells overcomes microenvironmental BCR- and CD40L- stimulation, antagonizes pro-survival AKT pathway and induces selective cytotoxicity to leukemia cells. PI3K p110delta/p110gamma blockade reduces TCR-induced T cell proliferation and cytokine production, suggesting PI3K p110delta/p110gamma have dual roles in the leukemic and normal immune compartment. PI3K p110delta/p110gamma inhibition does not impair natural killer cell- mediated cellular cytotoxicity. Most importantly, PI3K p110delta/p110gamma inhibition can overcome ibrutinib resistance due to the BTK C481S mutation. Using different genetic mouse models, we demonstrate that global inactivation of p110delta blocks leukemia development, confirming that p110delta is critical for CLL initiation and progression. Additionally, blocking p110delta activity in the microenvironment protects against both murine CLL and acute myeloid leukemia due to the lack of regulatory T cell immunosuppression. These data suggest a separate immunomodulatory effect of p110delta blockade independent of BCR signaling or direct tumor efficacy. Collectively, these data suggest p110delta blockade may have a broader immune modulatory role across other types of leukemia. 2017 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1503066319794882 http://rave.ohiolink.edu/etdc/view?acc_num=osu1503066319794882 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Pharmaceuticals
Immunology
Chronic lymphocytic leukemia
PI3K p110delta
spellingShingle Biomedical Research
Pharmaceuticals
Immunology
Chronic lymphocytic leukemia
PI3K p110delta
Dong, Shuai
Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia
author Dong, Shuai
author_facet Dong, Shuai
author_sort Dong, Shuai
title Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia
title_short Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia
title_full Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia
title_fullStr Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia
title_full_unstemmed Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia
title_sort pharmacologic and genetic investigation of pi3k p110delta in chronic lymphocytic leukemia
publisher The Ohio State University / OhioLINK
publishDate 2017
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1503066319794882
work_keys_str_mv AT dongshuai pharmacologicandgeneticinvestigationofpi3kp110deltainchroniclymphocyticleukemia
_version_ 1719452852231864320

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