EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4 T cells in chronic lymphocytic leukemia.

The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4 T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4 T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4 T cells, that is enriched in genes typical for T regulatory type 1 (T1) cells.

Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.

Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. Here, we perform multi-omic profiling of 60 glioblastoma primary tumours and use orthogonal analysis of chromatin and RNA-derived gene regulatory networks to identify 38 subtype master regulators, whose cell population-specific activities we further map in published single-cell RNA sequencing data. These analyses identify the oligodendrocyte precursor marker and chromatin modifier SOX10 as a master regulator in RTK I-subtype tumours.

Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype.

Elevated amino acid catabolism is common to many cancers. Here, we show that glioblastoma are excreting large amounts of branched-chain ketoacids (BCKAs), metabolites of branched-chain amino acid (BCAA) catabolism. We show that efflux of BCKAs, as well as pyruvate, is mediated by the monocarboxylate transporter 1 (MCT1) in glioblastoma.

Gcn5 Modulates the Cellular Response to Oxidative Stress and Histone Deacetylase Inhibition.

To identify chemical genetic interactions underlying the mechanism of action of histone deacetylase inhibitors (HDACi) a yeast deletion library was screened for hypersensitive deletion mutants that confer increased sensitivity to the HDACi, CG-1521. The screen demonstrated that loss of GCN5 or deletion of components of the Gcn5 histone acetyltransferase (HAT) complex, SAGA, sensitizes yeast to CG-1521-induced cell death. Expression profiling after CG-1521 treatment reveals increased expression of genes involved in metabolism and oxidative stress response, and oxidative stress response mutants are hypersensitive to CG-1521 treatment.

High throughput screening identifies modulators of histone deacetylase inhibitors.

Background: Previous studies from our laboratory and others have demonstrated that in addition to altering chromatin acetylation and conformation, histone deacetylase inhibitors (HDACi) disrupt the acetylation status of numerous transcription factors and other proteins. A whole genome yeast deletion library screen was used to identify components of the transcriptional apparatus that modulate the sensitivity to the hydroxamic acid-based HDACi, CG-1521.

Results: Screening 4852 haploid Saccharomyces cerevisiae deletion strains for sensitivity to CG-1521 identifies 407 sensitive and 80 resistant strains.

Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status.

Previous studies have suggested that 1,25 dihydroxyvitamin D(3) (1,25(OH)2D3) induces cell cycle arrest and/or apoptosis in prostate cancer cells in vitro, suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent. Most epidemiological data however shows a weak link between serum 25(OH)D3 and risk of prostate cancer. To explore this dichotomy we have compared tumor progression in the LPB-Tag model of prostate in VDR knock out (VDRKO) and wild type (VDRWT) mice.