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A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes

ABSTRACT: A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes

PROVIDER: PRJNA1258074 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33409200_1.fastq.gz	Fastqsanger.gz
	SRR33409200_2.fastq.gz	Fastqsanger.gz
	SRR33409300_1.fastq.gz	Fastqsanger.gz
	SRR33409300_2.fastq.gz	Fastqsanger.gz
	SRR33409201_1.fastq.gz	Fastqsanger.gz

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A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes

Project description:We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.

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Project description:Activation of G protein-coupled estrogen receptor 1 (GPER1) is an attractive therapeutic strategy to treat a variety of human diseases, including cancer. Here, we show that GPER1 is remarkably upregulated in tumor cells derived from different cohorts of Waldenström Macroglobulinemia (WM) patients respect to normal B cells. Using the clinically relevant GPER1-selective small-molecule agonist G-1 (also named Tespria), we demonstrate that pharmacological activation of GPER1 leads to G2/M cell cycle arrest and apoptosis both in vitro and in vivo in animal model, even in the context of the protective bone marrow milieu. We report that activation of GPER1 triggers the TP53 pathway, which remains actionable during WM progression. This study identifies a novel druggable target in WM and paves the way for the clinical development of the GPER1 agonist G-1.

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Project description:Waldenström macroglobulinemia (WM), is a rare non-Hodgkin lymphoma preceded by a clinically asymptomatic benign monoclonal gammopathy of undetermined significance (IgM-MGUS). The factors underlying the malignant progression between these two IgM-monoclonal gammopathies remain poorly understood. The non-coding genome is increasingly recognized as an important driver of disease pathogenesis, and there remains a lack of exploration of the influence of non-coding RNAs within the IgM-monoclonal gammopathy disease spectrum. The present study explores the role of microRNA (miRNA) and long non-coded RNA (lncRNA) in IgM-gammopathies and specifically elucidates potentially regulated protein-coding genes and pathways. A comprehensive analysis of miRNA, lncRNA and protein-coding coding genes was conducted on 28 subjects, 17 patients with WM, 6 patients with IgM-MGUS, and 5 normal controls. Differential expression analysis revealed a number of dysregulated miRNA and lncRNA between IgM-gammopathies compared to normal controls and specifically between IgM-MGUS and WM. Pathway analysis was conducted utilizing differentially expressed mRNA with correlated biological expression of targeting miRNA. Here, a number of pathways were implicated influencing a gamut of cellular functions, including cell signaling, metabolism, replication, and immune regulation in both WM compared to IgM-MGUS and IgM-gammopathies compared to controls. This report is additionally one of the first published analyses of lncRNAs in WM, where we demonstrate a number of lncRNA associated with transcription and apoptosis regulation genes in WM compared to IgM-MGUS. This study highlights the role of non-coding RNA in IgM-gammopathies and the potential to recognize novel targets which may halt or slow the malignant progression between these two diseases.

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