The development of mature B lymphocytes requires the combined function of CD19 and the p110δ subunit of PI3K

Kövesdi, Dorottya; Bell, Sarah E.; Turner, Martin

doi:10.4161/self.1.2.11796

Cited by 8 publications

(5 citation statements)

References 57 publications

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“…This was surprising given that mb1Cre control autoreactive mice displayed a large MZ B cell subset, larger than in nonautoreactive mice. Moreover, a sizable body of literature indicates that PI3K activity in B cells positively correlates with MZ B cell formation (Anzelon et al, 2003; Durand et al, 2009; Chen et al, 2010; Kövesdi et al, 2010; So et al, 2013). In fact, the splenic B cell population of nonautoreactive (H-2 d ) P110* mice was enriched in MZ B cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

Greaves

Peterson

Strauch

et al. 2019

Journal of Experimental Medicine

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Section: Resultsmentioning

confidence: 99%

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

Greaves

Peterson

Strauch

et al. 2019

Journal of Experimental Medicine

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“…The connecting molecule between BCR and PI3K cassette in normal B-cells was Syk (11). In concert with PI3K, CD19 initiated signal transduction pathway (12) and MAPK down-stream cascade appear to be essential in mature B-lymphocyte development and maintenance (13). Finally, Ras-Raf-MAPK and PI3K-mTOR signaling, albeit in solid tumors, have been indicated to be primary nodes in tumorigenesis (14).…”

Section: Introductionmentioning

confidence: 99%

Idelalisib Impacts Cell Growth through Inhibiting Translation-Regulatory Mechanisms in Mantle Cell Lymphoma

Yang

Chen

et al. 2017

Clinical Cancer Research

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Purpose PI3 Kinase is a critical node in the B-cell receptor pathway which is responsible for survival and proliferation of B-cell malignancies. Idelalisib, a PI3Kδ-isoform specific inhibitor, has been approved to treat B-cell malignancies. While biological activity of the drug has been evaluated, molecular mechanisms and signaling pathway disruption leading to the biological effects of idelalisib are not yet well-defined. Prior laboratory reports have identified transcription and translation as the primary events for attenuation of PI3Kα isoform. We hypothesized that PI3Kδ-isoform inhibition by idelalisib should also affect gene transcription and protein translation. Experimental Design Using three mantle cell lymphoma cell lines and primary cells from patients, biological consequences such as apoptosis/cell cycle analysis, as well as RNA/protein synthesis were evaluated. Proteomics analyses (RPPA and immunoblot assays) defined molecular events downstream of PI3K/AKT cassette. Results Idelalisib treatment resulted in inhibition of protein synthesis, which correlated with reduction in cell size and cell growth. A moderate loss of viability without any change in cell cycle profile was observed. Idelalisib treatment inhibited AKT activation, an immediate downstream PI3K effector, and also reduced phosphorylation levels of downstream AKT/mTOR pathway proteins such as PRAS40. In addition, idelalisib treatment impeded activation of the MAPK pathway, and MEK, ERK and p90RSK phosphorylation levels were reduced. Reduction in AKT, PDK1, and MEK phosphorylation correlated with protein synthesis inhibition. Conclusions Collectively, these results clarify the molecular mechanisms of actions and may provide biomarkers and targets for combination with idelalisib in B-cell malignancies.

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“…Mature B cells were identified as double positive B220/IgM population of splenocytes (32, 43). The spleens from homozygous mutant animals were smaller compared to the wild-type spleen.…”

Section: Resultsmentioning

confidence: 99%

Sprague Dawley Rag2-Null Rats Created from Engineered Spermatogonial Stem Cells Are Immunodeficient and Permissive to Human Xenografts

Noto¹,

Adjan-Steffey

Tong

et al. 2018

Molecular Cancer Therapeutics

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The rat is the preferred model for toxicology studies, and it offers distinctive advantages over the mouse as a preclinical research model including larger sample size collection, lower rates of drug clearance, and relative ease of surgical manipulation. An immunodeficient rat would allow for larger tumor size development, prolonged dosing and drug efficacy studies, and preliminary toxicologic testing and pharmacokinetic/pharmacodynamic studies in the same model animal. Here, we created an immunodeficient rat with a functional deletion of the Recombination Activating Gene 2 () gene, using genetically modified spermatogonial stem cells (SSC). We targeted the gene in rat SSCs with TALENs and transplanted these-deficient SSCs into sterile recipients. Offspring were genotyped, and a founder with a 27 bp deletion mutation was identified and bred to homozygosity to produce the Sprague-Dawley - (SDR) knockout rat. We demonstrated that SDR rat lacks mature B and T cells. Furthermore, the SDR rat model was permissive to growth of human glioblastoma cell line subcutaneously resulting in successful growth of tumors. In addition, a human KRAS-mutant non-small cell lung cancer cell line (H358), a patient-derived high-grade serous ovarian cancer cell line (OV81), and a patient-derived recurrent endometrial cancer cell line (OV185) were transplanted subcutaneously to test the ability of the SDR rat to accommodate human xenografts from multiple tissue types. All human cancer cell lines showed efficient tumor uptake and growth kinetics indicating that the SDR rat is a viable host for a range of xenograft studies..

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The development of mature B lymphocytes requires the combined function of CD19 and the p110δ subunit of PI3K

Cited by 8 publications

References 57 publications

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

Idelalisib Impacts Cell Growth through Inhibiting Translation-Regulatory Mechanisms in Mantle Cell Lymphoma

Sprague Dawley Rag2-Null Rats Created from Engineered Spermatogonial Stem Cells Are Immunodeficient and Permissive to Human Xenografts

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