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Acta Biochimica Et Biophysica Sinica Nov 2023Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the...
Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the pathogenesis of ulcerative colitis at the single-cell level and unveil its clinical significance. Using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis, we identify a subpopulation of plasma cells (PCs) with significantly increased infiltration in UC colonic mucosa, characterized by pronounced oxidative stress. Combining 10 machine learning approaches, we find that the PC oxidative stress genes accurately distinguish diseased mucosa from normal mucosa (independent external testing AUC=0.991, sensitivity=0.986, specificity=0.909). Using MCPcounter and non-negative matrix factorization, we identify the association between PC oxidative stress genes and immune cell infiltration as well as patient heterogeneity. Spatial transcriptome data is used to verify the infiltration of oxidatively stressed PCs in colitis. Finally, we develop a gene-immune convolutional neural network deep learning model to diagnose UC mucosa in different cohorts (independent external testing AUC=0.984, sensitivity=95.9%, specificity=100%). Our work sheds light on the key pathogenic cell subpopulations in UC and is essential for the development of future clinical disease diagnostic tools.
Topics: Humans; Colitis, Ulcerative; Plasma Cells; Deep Learning; Gene Expression Profiling; Intestinal Mucosa
PubMed: 37814814
DOI: 10.3724/abbs.2023237 -
Frontiers in Immunology 2023Multiple myeloma (MM) is a devastating plasma cell malignancy characterized by the expansion of aberrant monoclonal plasma cells in the bone marrow, leading to severe...
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. 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.
Topics: Humans; Animals; Mice; Multiple Myeloma; Protein-Arginine N-Methyltransferases; Plasma Cells; Antiviral Agents; Apoptosis; Repressor Proteins
PubMed: 37600810
DOI: 10.3389/fimmu.2023.1239614 -
Medicine Dec 2023Multiple myeloma (MM) is the second most prevalent hematological malignancy and is distinguished by the aberrant proliferation of monoclonal plasma cells inside the bone... (Review)
Review
Multiple myeloma (MM) is the second most prevalent hematological malignancy and is distinguished by the aberrant proliferation of monoclonal plasma cells inside the bone marrow and production of M-protein. This condition frequently results in bone deterioration, acute kidney damage, anemia, and hypercalcemia. However, the clinical manifestations and accompanying symptoms of MM vary and may change as the condition evolves. Therefore, diagnosis of MM is difficult. At present, the confirmation of MM diagnosis necessitates the use of bone marrow biopsy, a procedure that is both invasive and challenging for assessing dynamic alterations in the disease. The integration of laboratory testing technologies with imaging technology has the potential to enhance the diagnostic effectiveness and provide a thorough evaluation of disease progression and prognosis in patients with MM. All the examination methods have advantages and disadvantages. Therefore, diagnosis is determined by the application of clinical characteristics, serological tests, and imaging investigations.
Topics: Humans; Multiple Myeloma; Bone Marrow; Plasma Cells; Diagnostic Imaging; Bone and Bones
PubMed: 38206744
DOI: 10.1097/MD.0000000000036660 -
Research Square Aug 2023Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors...
Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers have been identified. One of these markers, , epigenetically regulates cell cycle and other processes and has already been studied using RNA-seq. In this study a massive (325,025 cells and 49 patients) single cell multiomic dataset was generated with jointly quantified ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identified an association between one plasma cell subtype with myeloma progression that we have called relapsed/refractory plasma cells (RRPCs). These cells are associated with 1q alterations, TP53 mutations, and higher expression of . We also identified downstream regulation of cell cycle inhibitors in these cells, possible regulation of the transcription factor (TF) PBX1 on 1q, and determined that may be acting primarily through this subset of cells.
PubMed: 37645789
DOI: 10.21203/rs.3.rs-3221549/v1 -
BioRxiv : the Preprint Server For... Apr 2024Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control...
Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control LLPC specification and survival remain poorly resolved. Using intra-vital two-photon imaging, we find that in contrast to most plasma cells in the bone marrow, LLPCs are uniquely sessile and organized into clusters that are dependent on April, an important survival factor. Using deep, bulk RNA sequencing, and surface protein flow-based phenotyping, we find that LLPCs express a unique transcriptome and proteome compared to bulk PCs, fine tuning expression of key cell surface molecules, CD93, CD81, CXCR4, CD326, CD44 and CD48, important for adhesion and homing, and phenotypically label LLPCs within mature PC pool. Conditional deletion of Cxcr4 in PCs following immunization leads to rapid mobilization from the BM, reduced survival of antigen-specific PCs, and ultimately accelerated decay of antibody titer. In naive mice, the endogenous LLPCs BCR repertoire exhibits reduced diversity, reduced somatic mutations, and increased public clones and IgM isotypes, particularly in young mice, suggesting LLPC specification is non-random. As mice age, the BM PC compartment becomes enriched in LLPCs, which may outcompete and limit entry of new PC into the LLPC niche and pool.
PubMed: 36891288
DOI: 10.1101/2023.02.15.527913 -
Nature Immunology Jun 2024Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of...
Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using single-cell RNA sequencing and B cell antigen receptor sequencing in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveals a new PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters in the GC.
Topics: Animals; Plasma Cells; Mice; Germinal Center; Cell Differentiation; Receptors, Antigen, B-Cell; Mice, Inbred C57BL; Receptors, Immunologic; Mice, Transgenic
PubMed: 38698087
DOI: 10.1038/s41590-024-01831-y -
Frontiers in Medicine 2024Granulomatous lobular mastitis (GLM) is a rare inflammatory breast disease with unknown etiology, characterized by non-caseous granulomatous inflammation of the lobules,... (Review)
Review
Granulomatous lobular mastitis (GLM) is a rare inflammatory breast disease with unknown etiology, characterized by non-caseous granulomatous inflammation of the lobules, which infiltrate lymphocytes, neutrophils, plasma cells, monocytes, and eosinophils may accompany. GLM is often misdiagnosed as breast cancer due to the lack of specificity in clinical and imaging examinations, and therefore histopathology is the main basis for confirming the diagnosis. This review provides an overview of the pathological features of granulomatous lobular mastitis and cystic neutrophil granulomatous mastitis (CNGM, a pathologic subtype of GLM). As well as pathologic manifestations of other breast diseases that need to be differentiated from granulomatous lobular mastitis such as breast tuberculosis, lymphocytic mastopathy/diabetic mastopathy, IgG4-related sclerosing mastitis (IgG4-RSM), nodular disease, Wegener's granulomatosis, and plasma cell mastitis. Besides, discusses GLM and CNGM, GLM and breast cancer, emphasizing that their relationship deserves further in-depth exploration. The pathogenesis of GLM has not yet been clearly articulated and needs to be further explored, pathology enables direct observation of the microscopic manifestations of the disease and contributes to further investigation of the pathogenesis.
PubMed: 38371511
DOI: 10.3389/fmed.2024.1326587 -
Journal of Immunology (Baltimore, Md. :... Jan 2024Serum Ab concentrations, selection for higher affinity BCRs, and generation of higher Ab affinities are important elements of immune response optimization and functions...
Serum Ab concentrations, selection for higher affinity BCRs, and generation of higher Ab affinities are important elements of immune response optimization and functions of germinal center (GC) reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by mouse GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether glucose uptake or glycolysis increases in GC B cells compared with their naive precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that reduction of the glucose transporter GLUT1 in mice after establishment of a preimmune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and plasma cell outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway, whose activity was important in controlling reactive oxygen species (ROS) and Ab-secreting cell production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose, an efficient precursor to glycosylation, supported robust production of and normal Ab secretion by Ab-secreting cells under glucose-free conditions. Collectively, the findings indicate that GCs depend on normal glucose influx, especially in plasma cell production, but reveal an unexpected metabolic flexibility in hexose requirements.
Topics: Mice; Animals; Glucose; Reactive Oxygen Species; Germinal Center; Antibodies; Cell Differentiation
PubMed: 37955416
DOI: 10.4049/jimmunol.2200756 -
Leukemia Sep 2023UTX/KDM6A, a histone H3K27 demethylase and a key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor suppressor function...
UTX/KDM6A, a histone H3K27 demethylase and a key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor suppressor function remains largely uncharacterized in multiple myeloma (MM). Here, we show that the conditional deletion of the X-linked Utx in germinal center (GC) derived cells collaborates with the activating Braf mutation and promotes induction of lethal GC/post-GC B cell malignancies with MM-like plasma cell neoplasms being the most frequent. Mice that developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow and extramedullary organs, serum M proteins, and anemia. Add-back of either wild-type UTX or a series of mutants revealed that cIDR domain, that forms phase-separated liquid condensates, is largely responsible for the catalytic activity-independent tumor suppressor function of UTX in MM cells. Utx loss in concert with Braf only slightly induced MM-like profiles of transcriptome, chromatin accessibility, and H3K27 acetylation, however, it allowed plasma cells to gradually undergo full transformation through activation of transcriptional networks specific to MM that induce high levels of Myc expression. Our results reveal a tumor suppressor function of UTX in MM and implicate its insufficiency in the transcriptional reprogramming of plasma cells in the pathogenesis of MM.
Topics: Animals; Mice; B-Lymphocytes; Genes, Tumor Suppressor; Germinal Center; Histone Demethylases; Multiple Myeloma; Proto-Oncogene Proteins B-raf
PubMed: 37198323
DOI: 10.1038/s41375-023-01928-7