Dataset Information

ChIP-seq analysis for H3K4me3, H3K27ac, H3K27me3, p-STAT3, POU2AF1 and ELL2 in MM.1S cells

ABSTRACT: Multiple myeloma (MM) is a plasma cell neoplasm that depends on the bone marrow (BM) microenvironment; however, the underlying mechanisms of epigenetic contribution to the pathogenesis of MM are incompletely understood. Here, we delineate the epigenetic-driven transcriptional and splicing program crucial for MM. We recharacterized transcriptional program induced by IL-6/JAK/STAT3 pathway by ChIP-seq and RNA-seq analyses combined with CRIPSR knockout screening database, and identified B cell lineage factors, POU2AF1 and ELL2, as crucial IL-6/JAK/STAT3 targets that are essential for MM cell growth and survival. Genetic depletion of these factors suppressed MM cell growth in vitro and in the xenograft model of IL-6 humanized mice. Mechanistically, POU2AF1 and ELL2 govern MM-distinct transcriptional program representing immaturity, and IL-6/JAK/STAT3 pathway augments this program through upregulating and recruiting these factors to the MM-signature genes. Furthermore, we showed that IL-6 induces alternative splicing that is partly mediated by POU2AF1. Proteomic study identified novel POU2AF1-associated factors that converge in regulation of RNA, including RNA splicing. Indeed, POU2AF1 is adjacent to multiple splicing factors required for MM cell survival and is involved in the organization of nuclear speckles. Finally, we showed that gapmer antisense oligonucleotides (ASOs) targeting POU2AF1 inhibit its expression and MM cell growth in the presence of soluble BM stromal cell factors, including IL-6. Our data demonstrate that IL-6-driven B cell-lineage factors are the vulnerability of MM cells and may represent novel therapeutic targets for this incurable tumor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298692 | GEO | 2026/02/15

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) is characterized by constitutive activation of the NF-ÃªB pathway. Here we show that the NF- ÃªB pathway induces the expression of the cytokines IL-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated STAT3 protein, suggesting autocrine signaling. Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3. Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6 and/or IL-10, and their downstream targets. Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from GCB DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-kB activity, proliferation, and glycolysis. A smallmolecule inhibitor of JAK signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines, and synergized with an inhibitor of NF-kB signaling. These findings suggest that the biological interplay between the STAT3 and NF-kB pathways may be exploited for the treatments of a subset of ABC DLBCLs. Activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) cell lines were used as model systems to study the cytokine pathways in these cells. We expressed inducible IkB super-repressor for 1 to 24 hours to identify NF-kB target genes in OCI-Ly3 and OCI-Ly10 cells for a total of 13 arrays with replicates of each time point. We treated OCI-Ly3 cells with IL-10 for 1 to 96 hours for a total of 10 arrays with replicates of each time point. We treated OCI-Ly10 cells with IL-6 for 30 minutes to 24 hours for a total of 8 arrays with replicates of each time point. OCI-Ly10 cells transfected with no siRNA versus STAT3-siRNA for 8, 24, or 48 hours for a total of 5 arrays with replicates for 24 and 48 hours. We treated OCI-Ly10 cells with JAK inhibitor I for 3 and 6 hours for a total of 4 arrays with replicates of each time point.

Dataset Information

ChIP-seq analysis for H3K4me3, H3K27ac, H3K27me3, p-STAT3, POU2AF1 and ELL2 in MM.1S cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets