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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

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

Ali Ahmed Y AY Wu Xun X Eissa Nour N Hou Sen S Ghia Jean-Eric JE Murooka Thomas T TT Banerji Versha V Johnston James B JB Lin Francis F Gibson Spencer B SB Marshall Aaron J AJ

Leukemia 20180131 9

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 observ ...[more]

PMID: 29479062

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Project description:Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.

Dataset Information

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

Publications

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

Similar Datasets

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