Monocyte-derived dendritic cells response to mycobacterial glycolipid, phosphatidyl-inositol mannosides (PIM)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84740 | GEO | 2017/01/31
SECONDARY ACCESSION(S): PRJNA330976
REPOSITORIES: GEO
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Project description:The aim of the dataset was to study on genome-wide level the effect of PIM kinase (PIM1+PIM2+PIM3) knockdown in gene expression on early differentiation of human cord blood derived CD4+ T cells cultured under Th1 (Act+IL12) polarizing conditions. Total RNA from PIM1+PIM2+PIM3 siRNA treated cord blood CD4+ T cells 6 hours after culturing the cells in activating (antiCD3+antiCD28) plus IL-12 (Th1) or IL-4 (Th2) conditions was compared to total RNA from nonspecific control siRNA treated cells. Samples from 3 biological replicates were analysed.
2012-12-05 | E-GEOD-40542 | biostudies-arrayexpress
Project description:The aim of the dataset was to study on genome-wide level the effect of PIM kinase (PIM1+PIM2+PIM3) knockdown in gene expression on early differentiation of human cord blood derived CD4+ T cells cultured under Th1 (Act+IL12) polarizing conditions.
2012-12-05 | GSE40542 | GEO
Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using single shot DDA mass spectrometry we examine the impact of 24 hours treatment with two different pan-Pim kinase inhibitors PIM447 and AZD1208 on in vitro IL2 differentiated effector cytotoxic T lymphocytes. The Jak1/3 inhibitor tofacitinib was included as a control as this also blocks production of Pim kinases downstream of IL2. We find that treatment with pan-Pim kinase inhibitors has a similar phenotype to Pim1/Pim2 double deficiency, showing a reduction in proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecule Granzyme B and an increase in the translational repressor PDCD4.
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Project description:PIM serine/threonine kinases are overexpressed, translocated or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types, and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBLC), follicular lymphoma (FL), marginal zone lymphoma-MALT type (MZL-MALT), chronic lymphocytic leukemia (CLL) and nodal marginal zone lymphoma (NMZL) cases. Increased PIM2 protein expression was associated with an aggressive clinical course in ABC-DLBCL patients. Pharmacological and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity, and indicated the involvement of PIM2 kinase in regulating mTORC1. The simultaneous genetic inhibition of all three PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. Gene-expression profiling was conducted in a series of 114 B-cell non-Hodgkin lymphoma patients (DLBCL, FL, MALT, MCL, CLL and NMZL). Seven freshly frozen lymph nodes and six freshly frozen reactive tonsils were used as controls.
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Project description:PIM serine/threonine kinases are overexpressed, translocated or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types, and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBLC), follicular lymphoma (FL), marginal zone lymphoma-MALT type (MZL-MALT), chronic lymphocytic leukemia (CLL) and nodal marginal zone lymphoma (NMZL) cases. Increased PIM2 protein expression was associated with an aggressive clinical course in ABC-DLBCL patients. Pharmacological and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity, and indicated the involvement of PIM2 kinase in regulating mTORC1. The simultaneous genetic inhibition of all three PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.
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Project description:PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity in inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.
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Project description:Peripheral T cell lymphoma (PTCL) is a very aggressive disease which currently lacks efficient targeted therapy. New therapeutic strategies are needed to improve the very poor outcome of these patients. In these study we hypothesized that PIM kinases could be of therapeutic value in PTCL because we found an overexpression of PIM1 and PIM2, but not PIM3, in PTCL cases, cell lines and primary tumoral T cells from Sezary Syndrome patients, compared with reactive lymph nodes and normal T cells from healthy donors, respectively. In order to understand the mechanism of action of this pan-PIM inhibitor in PTCL, 4 cell lines (DERL7, HuT78, SR786 and MyLa) were treated with 10 μM of ETP-39010 for 0, 2, 4, 6, 10 and 24 h, and gene expression profiling was performed.
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Project description:Histone deacetylases (HDACs) have emerged as therapeutic targets in multiple myeloma (MM); however, the underlying roles of each class- or isoform-HDAC have not fully clarified. The present study delineates the effect of HDAC1 suppression or inhibition in MM cells. The RNA-seq analysis here revealed that HDAC1 suppression downregulated IRF4 and PIM2, which both play a crucial role in MM cell survival and proliferation. Mechanistically, HDAC1 inhibition dampens IRF4 transcription through histone hyperacetylation and hindrance of RNA polymerase II recruitment at IRF4 locus. PIM2 is transcriptionally under direct regulation by IRF4, thereby reducing PIM2 expression after HDAC1 inhibition. PIM2 is upregulated by the stimuli from bone marrow microenvironment including IL-6 independent of IRF4 regulation in MM cells. Although these stimuli reduce the cytotoxic effect of HDAC1 inhibition in MM cells, direct blockade of PIM2 overcomes the weak point of HDAC1 inhibition. The effect of the combination of class I HDAC inhibitors with PIM inhibitors is further confirmed in vivo mouse xenograft models. Our findings provoke clinical applications of class I HDAC inhibitors in combination with PIM inhibitors against MM.
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Project description:The PIM kinase family (PIM1, 2 and 3) play a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2’s role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. To better understand Off target effects of JP11646 and specific genes that have been directly or indirectly affected by JP11646, MM cell lines MM.1S and U266 were treated with JP11646 and then gene expression was analyzed.
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