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.
Project description:We found that a small molecule inhibitor of PRMT4 inhibited cell growth of a subset of multiple myeloma cell lines. To identify biomarkers that predict the sensitivity of myeloma cells to PRMT4 inhibition, we performed transcriptomic analysis of multiple myeloma cell lines.
Project description:Evaluation of anti-myeloma effects of inhibition of PRMT5, involved in arginine methylation. Three human multiple myeloma cell lines were treated with the PRMT5 inhibitor EPZ015938. Transcriptional profiles were compared to untreated controls.
Project description:ChIP-Seq of RNA Polymerase II, and transcriptional regulators in multiple myeloma (MM.1S), glioblastoma (U87-MG), and small cell lung carcinoma (H2171) treated with the BET bromodomain inhibitor JQ1. Cell lines (MM.1S, U87-MG, and H2171) representing multiple myeloma, glioblastoma, and small cell lung carcinoma, were treated with varying concentrations (5nM to 5µM) of the BET bromodomain inhibitor JQ1 followed by ChIP-Seq for RNA Polymerase II and transcriptional regulators. Other datasets from this series of experiments have been release as a part of GSE42355.
