Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells
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ABSTRACT:
PROVIDER: PRJNA311552 | ENA |
REPOSITORIES: ENA
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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.
| S-EPMC5382874 | biostudies-literature
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. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours
2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress
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.
| 2109499 | ecrin-mdr-crc
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.
2023-10-04 | GSE214871 | GEO
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: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.
2020-09-07 | GSE105439 | GEO
Project description:Hyperactivation of phosphatidylinositol-3 kinase (PI3K) signaling is a prominent feature in cancer cells. However, the mechanism underlying malignant behaviors in the state remains unknown. Here, we describe a mechanism of cancer drug resistance through protein synthesis pathway, downstream of PI3K signaling. An optogenetic tool (named PPAP2) controlling the PI3K signaling was developed. Melanoma cells stably expressing PPAP2 (A375-PPAP2) acquired resistance to a cancer drug in the hyperactivation state. Proteome analyses revealed that expression of the antiapoptotic factor tumor necrosis factor alpha–induced protein 8 (TNFAIP8) was upregulated. The TNFAIP8 upregulation was mediated by protein translation from pre-existing mRNA. These results suggest that cancer cells escape death via upregulation of TNFAIP8 expression from pre-existing mRNA even though alkylating cancer drugs damage DNA.
2022-11-01 | GSE212748 | GEO
Project description:Combining direct anti-tumor effects with targeting of tumor microenvironment is an attractive strategy that may lead to more effective therapies for advanced melanoma. Here, we tested whether association of TRAIL with co-targeting of MEK and PI3K/mTOR, or with MEK blockade, could have synergistic anti-melanoma activity mediated not only by induction of tumor cell death, but also by effects on the tumor microenvironment. Drug interaction analysis by the Chou-Talalay approach in a panel of 21 melanoma cell lines indicated that strong synergism could be achieved by association of the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor NPV-BEZ235 and TRAIL, as well as by the AZD6244/TRAIL combination. Synergism was observed on most tumors including TRAIL- or inhibitor-resistant melanomas, irrespective of the BRAF, NRAS, p53 and PTEN status, and was explained by enhanced induction of caspase-dependent melanoma apoptosis. The AZD/BEZ/TRAIL and AZD/TRAIL combinatorial treatments induced strong modulation of key apoptosis regulators along the extrinsic and intrinsic cell death pathways, including c-FLIP down-regulation, caspase-8 cleavage, BIMs and BAXa upregulation, clusterin and Mcl-1 inhibition, enhanced mitochondrial depolarization, suppression of inhibitors of apoptosis c-IAP1, c-IAP2, XIAP and Apollon, and caspase 3/7 activation. In an in vivo model, the AZD6244/TRAIL combinatorial treatment induced highly significant growth inhibition of a TRAIL-resistant tumor associated not only with melanoma cell death, but even with suppression of pro-angiogenic molecules HIF1a, VEGFa, IL-8 and TGFb1, and with inhibition of tumor angiogenesis. These results provide a proof of principle supporting the rationale for combinatorial treatments with synergistic anti-melanoma activity based on direct and indirect anti-tumor effects. The human melanoma cell line Me13 was established in our laboratory from a surgical specimen. Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 10% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37°C in a water-saturated atmosphere of 5% CO2 in air. 3x10^6 cells were seeded in 75 cm2 flasks; after 24 hours, cells were left untreated or treated with Selumetinib (Selleck Chemicals, Houston, TX) at 0.1 micromol/L, NVP-BEZ-235 (Selleck Chemicals, Houston, TX) at 0.1 micromol/L and sTRAIL (AdipoGen) at 25ng/ml as single drugs or in combination for 8 hours. Each treatment or combination was performed in triplicate. At the end of treatment, cells were collected and RNA extracted.
2014-10-08 | E-GEOD-55050 | biostudies-arrayexpress
Project description:While thousands of previously unannotated small and alternative open reading frames (alt-ORFs) have recently been revealed in the human genome, the functions of only a handful are currently known, leaving open the question of their biological significance as a class. Using a proteomic strategy for discovery of unannotated short open reading frames in human cells, we report the detection of alt-RPL36, a 148-amino acid protein co-encoded with and overlapping human RPL36. Alt-RPL36 interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 in HEK 293T cells increased PI(4,5)P2 levels in the plasma membrane and upregulated the PI3K-AKT-mTOR signaling pathway. Remarkably, we find that four serine residues of alt-RPL36 are phosphorylated, and mutation of these four serines to alanine abolished the interaction with TMEM24 and regulation of PI3K signaling. These results implicate alt-RPL36 as a novel regulator of PI(4,5)P2 synthesis upstream of the PI3K-AKT-mTOR signaling pathway, and the first example of a phosphorylated alt-ORF product. More broadly, both alt-RPL36 and RPL36 regulate protein synthesis and cell growth via different molecular mechanisms – AKT signaling and ribosome composition, respectively. One human transcript can therefore express two sequence-independent polypeptides from overlapping ORFs that regulate the same processes via distinct mechanisms.
2020-12-07 | PXD018268 | Pride