PIM447 treatment in T-ALL PDX splenocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145165 | GEO | 2020/02/17
REPOSITORIES: GEO
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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. 4 PTCL cell lines (DERL7, HuT78, SR786 and MyLa) were treated with DMSO and 10 μM of the pan-PIM inhibitor ETP-39010, and hybridized using the Universal Human Reference RNA (Stratagene, La Jolla, CA) as the reference sample.
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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: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.
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