Decoding Plasma Cell Maturation Dynamics with BCMA
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ABSTRACT:
PROVIDER: PRJNA1159213 | ENA |
REPOSITORIES: ENA
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Project description:Plasma cells provide protective antibodies following an infection or vaccination. A network of intrinsic and extrinsic factors fine-tunes the generation of a heterogenous plasma cell pool with varying metabolic requirements, transcriptional profiles and lifespans. Among these intrinsic factors, the B cell maturation antigen (BCMA) has been implicated in APRIL-mediated survival of long-lived plasma cells. Therefore, we introduced a tdTomato reporter into the Tnfrsf17 (BCMA) locus, to decode the developmental steps behind the generation of mature plasma cell subsets. We demonstrate that the BCMA:Tom reporter is exclusively detected in plasma cells, with its expression differing between IgH isotypes and increasing with plasma cell maturity. Combined with a Blimp1-GFP reporter, the BCMA:Tom reporter allowed us to track the step-wise maturation from newly formed to late plasma cells in various plasma cell subpopulations. Notably, in vitro-stimulated B cells induce BCMA only after adoptive transfer into recipient mice, emphasizing the impact of the in vivo microenvironment in establishing a mature plasma cell compartment. The BCMA:Tom reporter mouse provides a robust tool for tracking plasma cell development and maturation with flow cytometry or advanced imaging techniques, enabling a deeper understanding of the mechanisms regulating plasma cell heterogeneity and longevity.
2025-04-02 | GSE276846 | GEO
Project description:Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the clinical treatment of hematological malignancies due to the prominent anti-tumor effects. B-cell maturation antigen (BCMA) CAR-T cells have demonstrated promising effects in patients with relapsed/refractory multiple myeloma. However, the dynamics of CAR-T cell proliferation and cytotoxicity in a patient remains largely unexplored. Single-cell RNA sequencing samples were collected at three phases: CAR-T products before infusion, CAR-T on day 8 after infusion, and CAR-T on day 15 after infusion. After obtaining the PBMCs for each phase, CAR-T and endogenous T cells were collected by fluorescence-activated cell sorting with anti-Mouse IgG Biotin, FITC Streptavidin, and anti-human CD3 APC.
2020-10-01 | GSE151310 | GEO
Project description:Maturation of Long Lived Plasma cells
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Project description:Translational dynamics during seed maturation
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Project description:B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). We describe the case of a MM patient, enrolled in the CARTITUDE-1 trial (NCT03548207), who developed a progressive movement disorder with features of parkinsonism approximately three months after BCMA-targeted ciltacabtagene autoleucel CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We demonstrate BCMA expression on neurons and astrocytes in the basal ganglia of the patient. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting this may be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade ≥3 parkinsonism on the phase 2 cilta-cel trial and of grade 3 parkinsonism in the idecabtagene vicleucel (ide-cel) package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.
2021-08-27 | GSE182527 | GEO
Project description:We analysed the polysomal mRNA and total mRNA during Col-0 seed maturation The aim was to investigate the translational dynamics during seed maturation.
2019-09-28 | GSE127509 | GEO
Project description:Chimeric antigen receptor T-cells (CAR-T) targeting B-cell-maturating-antigen (TNRFSF17, BCMA) show unprecedented overall response rates of up to 100% in heavily pretreated relapsed-refractory Multiple Myeloma (RRMM). However, the efficiency of the treatment is hindered by the rapid emergence of tumor-intrinsic mechanisms of resistance. We herein describe a patient with RRMM and extramedullary disease (EMD) who underwent Idecabtagene vicleucel BCMA CAR-T therapy. The patient rapidly achieved very good partial response including full resolution of EMD, but aggressively relapsed 5 months after CAR T cell infusion. Single cell RNA sequencing and immunohistochemistry on the re-emerging tumor cells demonstrated loss of target expression on mRNA and protein levels, and whole genome sequencing revealed the homozygous deletion of Chr 16p1313, including the BCMA locus. Clonal heterogeneity of BCMA could be observed in 32 RRMM patients from our institution. In three of them heterozygous deletion of BCMA could be confirmed, with none of them having underwent prior anti-BCMA therapy. Thus, our report not only provides first evidence of BCMA loss as the underlying mechanism of disease relapse following BCMA targeted immunotherapy in MM. It furthermore identifies a subset of patients at risk to develop biallelic BCMA inactivation thus linking genomic instability in MM to relapse from targeted immunotherapies.
2020-12-30 | GSE143317 | GEO
Project description:Despite the acknowledged effectiveness of BCMA chimeric antigen receptor T (CAR-T) cells in killing multiple myeloma (MM) cells, predicting treatment responsivity to BCMA CAR-T therapy remains a challenge. In this study, we demonstrated that the best overall responses (BORs) of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells (Tregs), enhanced CD8+ effector T cell cytotoxic activity, and elevated type 1 conventional dendritic cell (cDC1) antigen presentation ability. Our study sheds light on MM microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.
2024-07-10 | GSE271915 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T. To examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk and single cell whole genome sequencing/ copy number variation analysis of 30 patients treated with anti-BCMA and/ or -GPRC5D CAR T/ TCE. In two cases, MM relapse post TCE/ CAR T was driven by BCMA negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected non-truncating missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCEs, despite detectable surface BCMA protein expression. Here, we also report the first four cases of MM relapse with biallelic mutations of GPRC5D following anti-GPRC5D TCE, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA or GPRC5D negative or mutant clones is an important tumor intrinsic driver of relapse post targeted therapies. Mutational events on BCMA confer distinct sensitivities towards different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
2023-06-29 | GSE226336 | GEO
Project description:Replication of the eukaryotic genome occurs in the context of chromatin, a nucleoprotein packaging state consisting of repeating nucleosomes. Chromatin is commonly thought to carry epigenetic information from one generation to the next, although it is unclear how such information survives the disruptions of nucleosomal architecture that occur during genomic replication. Here, we sought to directly measure a key aspect of chromatin structure dynamics during replication â?? how rapidly nucleosome positions are established on the newly-replicated daughter genomes. By isolating newly-synthesized DNA marked with the nucleotide analogue EdU, we characterize nucleosome positions on both daughter genomes of budding yeast during a time course of chromatin maturation. We find that nucleosomes rapidly adopt their mid log positions at highly-transcribed genes, and that this process was impaired upon treatment with the transcription inhibitor thiolutin, consistent with a role for transcription in positioning nucleosomes in vivo. Additionally, experiments in the Hir1-delta background reveal a role for HIR in nucleosome spacing. Using strand-specific EdU libraries, we characterize nucleosome positions on the leading and lagging strand daughter genomes, uncovering differences in chromatin maturation dynamics between the two daughter genomes at hundreds of genes. Our data define the maturation dynamics of newly-replicated chromatin, and support a role for transcription in sculpting the chromatin template. Gene expression array.
2016-08-25 | E-GEOD-79384 | biostudies-arrayexpress