Ontology highlight
ABSTRACT:
PROVIDER: PRJNA596656 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10738025_1.fastq.gz | Fastqsanger.gz | |||
| SRR10738025_2.fastq.gz | Fastqsanger.gz | |||
| SRR10738026_1.fastq.gz | Fastqsanger.gz | |||
| SRR10738026_2.fastq.gz | Fastqsanger.gz | |||
| SRR10738027_1.fastq.gz | Fastqsanger.gz |
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Project description:Light chain amyloidosis (AL) is a life-threatening plasma cell dyscrasia manifested by irreversible damage of multiple organs caused by monoclonal immunoglobulin light chain, production of pathogenic bone marrow plasma cells (BMPCs). Although AL is featured by both misfolding of monoclonal protein and plasma cell proliferation, the functional subclones and molecular mechanism of BMPCs in AL remain elusive. Also, inter-individual heterogeneities of AL determine the chemotherapy response and organ tropism of light chains, which require well-defined molecular subtypes. To address these, we conducted single-cell RNA sequencing (scRNA-seq) of BMPCs donated by patients with AL, patients with monoclonal gammopathy of undetermined significance (MGUS), and healthy controls. Single-cell transcriptome revealed a continuity of bone marrow plasma cell (BMPC) functional subclones, delineating DNA repair, cell proliferation, immunoglobulin production, etc., with the gradient of signaling entropy and immunoglobulin production. The amyloidosis-associated genes, such as the amyloid-beta binding Apolipoprotein E (APOE), Cystatin 3 (CST3), and Complement C1q A Chain (C1QA), were up-regulated in a subclone enriched in AL. The speculated light chain-producing subclones in AL up-regulated neutrophil degranulation pathways, transport to and modifications in Golgi apparatus, and asparagine N-linked protein glycosylation. Cyclin D1 (CCND1)hi AL, consisted of larger main subclones which highly expressed Bcl-2 complex and B-cell differentiation genes, was sensitive to venetoclax that targets Bcl-2. A major subset of CCND1low AL harbored larger carbohydrate-synthesizing subclone and up-regulated CCND2 and the amyloidosis-associated genes. Collectively, our results provided frontier insights into the functional subclones and molecular mechanism of BMPCs in AL, associated with amyloidosis, light chain production and venetoclax sensitivity, as knowledge for the future research on AL pathogenesis, AL subtypes and AL-specific therapies.
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Project description:Amyloidosis is a disorder characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis the most common form of amyloidosis can appear as a local disorder presented with mild symptoms or as a life threatening systemic disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this study, we investigated the protein composition of AL amyloid deposits isolated from human eyelid, conjunctival and orbital specimens. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were identified by liquid chromatography tandem mass spectrometry and subsequently quantified using the label-free mass spectrometry quantification method exponential modified Protein Abundance Index. Immunoglobulin light chain kappa or lambda was revealed to be the most predominant protein in the amyloid deposits. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provides high sensitivity and specificity of typing amyloidosis and may provide additional information on the pathology of amyloidosis.
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Project description:IGLV2-14 light chain sequences of patients with AL amyloidosis or multiple myeloma
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Project description:Amyloid deposition and neighboring tissue responses remain poorly understood. Twenty percent of patients with systemic light-chain amyloidosis (AL) have interstitial marrow amyloid containing clonal Ig light-chain fibrils and apolipoprotein chaperone proteins. We compared CD138-depleted aspirate mononuclear cells (MNC) from marrows of AL patients with (+MA) and without (-MA) interstitial amyloid by gene expression profiling (GEP) and single-cell RNA-sequencing (scRNA seq). GEP showed no differential expression of genes for proteolytic enzymes or apolipoproteins between the groups but +MA cases had significantly up-regulated erythroid genes involved in oxygen transport, including transmembrane and coiled-coil domain family 2 (TMCC2). In +MA marrows at the single-cell level, CD14+ monocytes were increased by 22%, granulocyte-monocyte progenitors decreased by 66%, and erythroid-megakaryocyte progenitors and early and late erythroid progenitors increased up to five-fold. Gene enrichment studies showed that in +MA marrows pathways for TNFα signaling, immune activation, monocyte hypoxia and erythropoiesis were significantly enriched. We also compared peripheral blood and marrow plasma by immunoprecipitation and immunoblot with respect to apolipoproteins and light chains in complex with the erythroid protein TMCC2, and by ELISA for marrow apolipoprotein E and J levels. Apolipoprotein J is strongly associated with light chains in blood and E is not, while in +MA marrow plasma J and E are strongly present in association with light chains. There is also significantly more apolipoprotein E and J in +MA marrow plasma. In summary, marrows with interstitial amyloid provide opportunities to study amyloid’s impact on cellular and regenerative activity and chaperone involvement in amyloid formation.
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