Biology subjects

Greiner, T.

Publications and source records attributed to Greiner, T..

4 recordsLinked to original sources

bioRxiv2026

Proteome landscape of B-cell malignancies identifies mantle cell lymphoma protein signature

Mantle cell lymphoma (MCL) is one of the deadliest forms of Non-Hodgkins B-cell lymphoma. Typically, patients present with both overexpression of CyclinD1 and secondary mutations identified by genomic sequencing. Although MCL patients may initially respond to treatment, they eventually relapse and succumb to disease, highlighting the essential need to identify new targets for treatment. Here we performed proteomic profiling of healthy B cells and three different forms of B-cell malignancies, including MCL, to define the proteomic signature of MCL. We compared the proteome of each to MCL and identified 10 proteins that are specifically upregulated in MCL. Of these 10 proteins, seven of them show no transcriptional changes and have been overlooked by conventional RNA expression analysis. Further analysis of the proteomic signature reveals potential avenues for dual targeting in CAR T-cell therapy and provides guidance for personalized therapeutics based on protein expression. STATEMENT OF SIGNIFICANCEWe present a resource defining the protein landscape of MCL, CLL, and FL as compared to healthy b cells identified utilizing quantitative proteomics from primary patient samples. Applied to MCL, our results identify 10 proteins specifically upregulated in MCL that may prove to be therapeutic targets to treat the disease.

cancer biology↗

bioRxiv2021

SARS-CoV-2 envelope-protein corruption of homeostatic signaling mechanisms in mammalian cells

During a SARS-CoV2 infection, host cells produce large amounts of the viral envelope protein (Ep-CoV2). Ep-CoV2 is partially inserted into the membrane of nascent viral particles and into cellular membranes. To mimic the pathophysiological impact of the cellular protein fraction, Ep-CoV2 was overexpressed in mammalian cells and effects on key signaling parameters were monitored. By tagging with green fluorescent protein (GFP), we found that Ep-CoV2 protein is mostly present in the endoplasmic reticulum with additional trace amounts in the plasma membrane. We observed that wild-type Ep-CoV2 and, to a lesser extent, its mutants (N15A, V25F) corrupted some of the most important homeostatic mechanisms in cells. The same was observed with isolated transmembrane domains of the protein. The Ep-CoV2-evoked elevation of intracellular Ca2+ and pH as well as the induced membrane depolarization produced by the presence of the protein interfere with major signal transduction cascades in host cells. These functions of Ep-CoV2, which likely contribute to the pathogenesis of the viral protein, result from the ion-channel activity of the viral protein. Two independent assays, a functional reconstitution of Ep-CoV2 protein in artificial membranes and a rescue of K+-deficient yeast mutants, confirm that Ep-CoV2 generates a cation-conducting channel with a low unitary conductance and a complex ion selectivity. The data presented here suggest that specific channel function inhibitors of Ep-CoV2 can provide cell protection and virostatic effects.

pathology↗

bioRxiv2019

Mechanism of gating and partial agonist action in the glycine receptor

The glycine receptor is a pentameric, neurotransmitter-activated ion channel that transitions between closed/resting, open and desensitized states. Glycine, a full agonist, produces an open channel probability (Po) of [~]1.0 while partial agonists, such as taurine and {gamma}-amino butyric acid (GABA) yield submaximal Po values. Despite extensive studies of pentameric Cys-loop receptors, there is little knowledge of the molecular mechanisms underpinning partial agonist action and how the receptor transitions from the closed to open and to desensitized conformations. Here we use electrophysiology and molecular dynamics (MD) simulations, together with a large ensemble of single particle cryo-EM reconstructions, to show how agonists populate agonist-bound yet closed channel states, thus explaining their lesser efficacy, yet also populate agonist-bound open and desensitized states. Measurements within the neurotransmitter binding pocket, as a function of bound agonist, provide a metric to correlate the extent of agonist-induced conformational changes to open channel probability across the Cys-loop receptor family.

neuroscience↗

bioRxiv2017

DNA copy number gains of TCF4 (E2-2) are associated with poor outcome and the activated B-cell-like subtype of diffuse large B-cell lymphoma

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by the chronic activation of signaling initiated by immunoglobulin- (IgM). By analyzing DNA copy profiles of 1,000 DLBCLs, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. We show that these alterations target the TCF4 (E2-2) transcription factor, and that over-expression of TCF4 leads to its occupancy on immunoglobulin gene enhancers and increased expression of IgM at the transcript and protein level. The TCF4 gene is one of the top BRD4-regulated genes in DLBCL. Using a BET proteolysis-targeting chimera (PROTAC) we show that TCF4 and IgM expression can be extinguished, and ABC-like DLBCL cells can be killed in vitro and in vivo. This highlights a novel genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

genomics↗