Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells
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ABSTRACT:
PROVIDER: PRJNA311552 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3160330.fastq.gz | Fastqsanger.gz | |||
| SRR3160340.fastq.gz | Fastqsanger.gz | |||
| SRR3160350.fastq.gz | Fastqsanger.gz | |||
| SRR3160360.fastq.gz | Fastqsanger.gz | |||
| SRR3160370.fastq.gz | Fastqsanger.gz |
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Project description:Activation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM). Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib inhibit PI3Kδ activity directly or indirectly through inhibition of the Bruton tyrosine kinase (BTK), thus possibly affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. These effects were both completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. Since such inhibitors are administered for years to patients, their genotoxic potential should be carefully considered while planning therapeutic protocols.
2017-01-31 | GSE77788 | GEO
Project description:Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.
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Project description:This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.
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Project description:We are examining the consequences of activating mutations in PI3K-delta in Th1 vs. Th2 differentiation. Using the house dust mite (HDM) model of allergic airway inflammation, which drives potent Th2 responses in vivo, we have found mice expressing hyper-activated PI3K-delta show impaired Th2 differentiation and instead favor Th1 cell differentiation. We would like to further investigate this aberrant CD4 differentiation profile using scRNA-seq to characterize PI3K-delta regulated aspects of type II immunity.
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Project description:Tumor-associated macrophages (TAMs) are involved in the pathogenesis of Hodgkin lymphoma (HL) and correlate with negative prognosis. The phosphatidylinositol 3-kinase (PI3K) mediates tumor and endothelial cell survival, and macrophage activation. As PI3Kδ and PI3Kγ are constitutively activated in HL, we describe RP6530, a novel PI3Kδ/γ inhibitor, in clinical development for HL and NHL. RP6530 exhibits anti-proliferative and cytotoxic activity both in vitro in HL cell lines and in vivo in HL xenograft mouse models. By inhibiting the metabolic regulator Pyruvate Kinase M2 (PKM2), RP6530 downregulates lactic acid metabolism in HL cells switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. RP6530 reshapes the tumor microenvironment (TME), through the re-polarization of TAMs into pro-inflammatory macrophages and the inhibition of tumor vasculature. These data demonstrate the central role of PI3K δ/γ inhibition for targeting HL cells and TME, indicating RP6530 as a novel therapeutic opportunity for HL patients.
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Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound.
2013-12-14 | GSE53309 | GEO
Project description:Reduced TCRγδ signal strength engages phosphatidylinositol 3-kinase (PI3K) to drive thymic development of IL-17A-secreting γδ T cells
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Project description:The prognosis of adult T-cell leukemia-lymphoma (ATL) remains very poor, and there is an urgent clinical need to investigate novel therapies for ATL. The expression of phosphatidylinositol 3-kinase-δ (PI3k-δ) is normally restricted to hematopoietic cells and is known as a key determinant of cell survival in certain cancers. The inhibitor of PI3k-δ, idelalisib, has been shown to be effective in the treatment of chronic lymphocytic leukemia. Here, we report the expression of PI3k-δ and the ability of idelalisib to promote apoptosis in ex vivo ATL samples. The activity of PI3K was quantified by a PI3-Kinase Activity ELISA kit. Although there was no significant difference in mean PI3K activity between healthy donors and patients with ATL, certain cases of ATL showed extremely high PI3K activities. The expression of PI3k-δ protein was detectable in most ATL cases. The freshly isolated cells from ATL patients were cultured with or without idelalisib for 0-10 days, and cell survival was then quantified. Idelalisib induced apoptosis in ATL cells in a time-dependent manner, and significantly reduced the frequency of viable ATL cells at 10 days. No time-dependent effects of idelalisib were observed in non-malignant T cells from the same patients. CCL22 has been reported to promote survival of ATL cells in part through the PI3K-AKT pathway. Idelalisib blocked this CCL22-induced phosphorylation of AKT and significantly inhibited the proliferation of ATL cells. These results validate the PI3K-AKT pathway as a potential therapeutic target in ATL.
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