Browsing by Author "Tran, Ngoc Tung"

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    Corrigendum: Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma
    (Frontiers Media, 2023-11-15) Nguyen, Hong Phuong; Le, Anh Quynh; Liu, Enze; Cesarano, Annamaria; DiMeo, Francesco; Perna, Fabiana; Kapur, Reuben; Walker, Brian A.; Tran, Ngoc Tung; Pediatrics, School of Medicine
    [This corrects the article DOI: 10.3389/fimmu.2023.1239614.].
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    Elucidating the Characteristics and Functionality of the Mouse Mucosal-Associated Mucosal Invariant T (MAIT) Cell Receptor
    (2023-08) Shrinivasan, Rashmi; Brutkiewicz, Randy R.; Dent, Alexander L.; Tran, Ngoc Tung
    Mucosal-associated invariant T cells (MAIT) are a subset of invariant, innate-like T-cells that are abundant in the gut lamina propria, kidney, lungs, and peripheral blood. MAIT cells are stimulated by the recognition of microbial vitamin B-derived metabolites by the MHC class I-like molecule, MR1. Recent studies have implicated MAIT cells in several autoimmune diseases, various cancers, and CNS disorders, making it essential to design animal models that replicate the human disease state. The relatively small population of MAIT cells in mice makes it difficult to isolate and characterize them. The MAIT cell receptor (TCR) is comprised of a Vα7.2-Jα33 rearrangement in humans and TRAV1-TRAJ33 in mice. This project aimed to create a tool to study mouse MAIT cells in detail by generating lentiviral plasmid constructs expressing cDNAs encoding the MAIT cell TCR α and β chains that will be ectopically expressed in TCR-deficient mouse T cells. A bulk TCR analysis of the mouse MR1-restricted MAIT hybridomas 6C2 and 8D12 was performed to confirm variable and joining regions in the TCR α and β chains. This analysis confirmed the proper MAIT cell TCR usage in the MAIT cell hybridomas. As both MAIT cell hybridomas can be stimulated by MR1-presented antigens, we obtained synthetic cDNAs that were generated for the TRAV1-TRAJ33 α chain and TRBV8.2 (TRBV13-2) β chain. These were subcloned into GFP- and mCherry-expressing plasmids and packaged into lentiviruses that will be used for transduction of TCR-deficient mouse T cells. Flow cytometry and ELISAs will ultimately be performed to confirm the functional expression of the MAIT cell TCR. These tools will greatly facilitate the investigation of MAIT cell function in vitro and the ultimate generation of retrogenic mice for the tracking of MAIT cells in vivo.
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    In vivo CRISPR/Cas9-mediated screen reveals a critical function of TFDP1 and E2F4 transcription factors in hematopoiesis
    (Springer Nature, 2024) Tran, Ngoc Tung; Graf, Robin; Acevedo-Ochoa, Ernesto; Trombke, Janine; Weber, Timm; Sommermann, Thomas; Salomon, Claudia; Kühn, Ralf; Rajewsky, Klaus; Chu, Van Trung; Pediatrics, School of Medicine
    Hematopoiesis is a continuous process of blood cell production driven by hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Proliferation and differentiation of HSPCs are regulated by complex transcriptional networks. In order to identify transcription factors with key roles in HSPC-mediated hematopoietic reconstitution, we developed an efficient and robust CRISPR/Cas9-based in vivo genetic screen. Using this experimental system, we identified the TFDP1 transcription factor to be essential for HSPC proliferation and post-transplant hematopoiesis. We further discovered that E2F4, an E2F transcription factor, serves as a binding partner of TFDP1 and is required for HSPC proliferation. Deletion of TFDP1 caused downregulation of genes associated with the cell cycle, with around 50% of these genes being identified as direct targets of TFDP1 and E2F4. Thus, our study expands the transcriptional network governing hematopoietic development through an in vivo CRISPR/Cas9-based genetic screen and identifies TFDP1/E2F4 as positive regulators of cell cycle genes in HSPCs.
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    Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma
    (Frontiers Media, 2023-08-04) Nguyen, Hong Phuong; Le, Anh Quynh; Liu, Enze; Cesarano, Annamaria; DiMeo, Francesco; Perna, Fabiana; Kapur, Reuben; Walker, Brian A.; Tran, Ngoc Tung; Pediatrics, School of Medicine
    Multiple myeloma (MM) is a devastating plasma cell malignancy characterized by the expansion of aberrant monoclonal plasma cells in the bone marrow, leading to severe clinical manifestations and poor prognosis, particularly in relapsed/refractory cases. Identifying novel therapeutic targets is crucial to improve treatment outcomes in these patients. In this study, we investigated the role of the protein arginine methyltransferase 1 (PRMT1) in MM pathogenesis and explored its potential as a therapeutic target. We observed that PRMT1, responsible for most asymmetric di-methylation in cells, exhibited the highest expression among PRMT family members in MM cell lines and primary MM cells. Importantly, PRMT1 expression was significantly elevated in relapsed/refractory patients compared to newly diagnosed patients. High expression of PRMT1 expression was strongly associated with poor prognosis. We found that genetic or enzymatic inhibition of PRMT1 impaired MM cell growth, induced cell cycle arrest, and triggered cell death. Treatment with MS023, a potent PRMT type I inhibitor, demonstrated a robust inhibitory effect on the viability of primary cells isolated from newly diagnosed and proteasome inhibitor-relapsed/refractory patients in a dose-dependent manner. Suppression of PRMT1 downregulated genes related to cell division and upregulated genes associated with apoptosis pathway. We also found that genes related to immune response and lymphocyte activation were significantly upregulated in PRMT1-suppressed cells. Notably, the activation status of T cells was strikingly enhanced upon co-culturing with PRMT1-KO MM cells. In vivo studies using a xenograft model revealed that targeting PRMT1 by either CRISPR/Cas9-mediated knockout or MS023 treatment significantly attenuated MM tumor growth and prolonged the survival of tumor-bearing mice. Histological analysis further confirmed increased apoptotic cell death in MS023-treated tumors. Collectively, our findings establish PRMT1 as an indispensable and novel therapeutic vulnerability in MM. The elevated expression of PRMT1 in relapsed/refractory patients underscores its potential as a target for overcoming treatment resistance. Moreover, our results highlight the efficacy of MS023 as a promising therapeutic agent against MM, offering new avenues for therapeutic approaches in relapsed/refractory MM.