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Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168951 | GEO | 2022/03/13

REPOSITORIES: GEO

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Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (bulkRNA-seq)

Project description:Purpose: We examined how transcriptional state changes relate to clonal selection as BRAF inhibitor resistance develops in BRAF-mutated myeloma. Methods: To this end we generated three single-cell clones from U266, a BRAFK601N -mutated myeloma cell line and DP6- a BRAFV600E myeloma cell line. All three U266 and DP6 clones were subjected to long-term dabrafenib treatment at their established IC50 doses (U266: 10uM, DP6 1nM). Bulk RNA-seq was performed before treatment, day 7, day 14, day 42 and at time of resistance. Results: Transcriptional adaptation after seven days was homogeneous for all clones, but was different across both cell lines. Oxidative phosphorylation (OxPhos) emerged as the most consistently enriched signaling pathway in persistent cells from both cell lines as compared to baseline. Conclusions: BRAF inhibition in BRAF-mutated myeloma cells leads to transcriptional reprogramming with induction of OxPhos-related genes within a brief period of time.

2022-03-13 | GSE168950 | GEO

Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (ChIP-seq)

Project description:Purpose: We examined the mechanisms of transcriptional adaptation in persistent cells and asked if transcriptional state changes can be attributed to alterations in enhancer activity. Methods: ChIPseq for the enhancer mark H3K27ac was performed in three single-cell clones derived from the multiple myeloma cell line U266 treted with dabrafenib vs. DMSO for 14 Results: We observed substantial epigenetic remodeling illustrated by a greater number of unique peaks in dabrafenib-persistent cells as compared to dabrafenib-naïve controls. Out of a total of 22756 merged peaks, which were called in at least three samples, 7645 (34%) were unique to persistent cells compared to 454 (2%) in untreated cells. Conclusions: Altered transcriptional states are associated with enhancer rewiring in drug-resistant myeloma

2022-03-13 | GSE168949 | GEO

Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (scRNA-seq)

Project description:Purpose: We here applied single-cell RNA sequencing of circulating MM cells from primary MM patients to perform transcriptional profiling of myeloma cells and study emerging resistance mechanisms in real-time. Methods: A total of 1509 single CD138+/CD38+ myeloma and normal plasma cells from three patients and one normal donor were examined by full-length single-cell RNA sequencing. Results: Quality filtering resulted in the retention of 1153 cells with an average of 4836 genes detected per cell. Rapid transcriptional adaptation was observed in the presence of BRAF/MEK inhibitor treatment. Conclusions: Inhibition of the BRAF/MEK pathway in myeloma patients induces cellular adaptation accompanied by metabolic resistance and preferential transcriptional activation of OxPhos.

2022-03-13 | GSE168948 | GEO

Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma

Project description:Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma

| PRJNA714647 | ENA

Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (ChIP-seq)

Project description:Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (ChIP-seq)

| PRJNA714651 | ENA

Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (scRNA-seq)

Project description:Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (scRNA-seq)

| PRJNA714650 | ENA

Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (bulkRNA-seq)

Project description:Transcriptional adaptation and enhancer rewiring promote metabolic resistance in BRAFmutated multiple myeloma (bulkRNA-seq)

| PRJNA714652 | ENA

Cereblon enhancer methylation and IMiD resistance in multiple myeloma.

Project description:Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.

| S-EPMC8569411 | biostudies-literature

P-body proteins regulate transcriptional rewiring to promote DNA replication stress resistance.

Project description:mRNA-processing (P-) bodies are cytoplasmic granules that form in eukaryotic cells in response to numerous stresses to serve as sites of degradation and storage of mRNAs. Functional P-bodies are critical for the DNA replication stress response in yeast, yet the repertoire of P-body targets and the mechanisms by which P-bodies promote replication stress resistance are unknown. In this study we identify the complete complement of mRNA targets of P-bodies during replication stress induced by hydroxyurea treatment. The key P-body protein Lsm1 controls the abundance of HHT1, ACF4, ARL3, TMA16, RRS1 and YOX1 mRNAs to prevent their toxic accumulation during replication stress. Accumulation of YOX1 mRNA causes aberrant downregulation of a network of genes critical for DNA replication stress resistance and leads to toxic acetaldehyde accumulation. Our data reveal the scope and the targets of regulation by P-body proteins during the DNA replication stress response.P-bodies form in response to stress and act as sites of mRNA storage and degradation. Here the authors identify the mRNA targets of P-bodies during DNA replication stress, and show that P-body proteins act to prevent toxic accumulation of these target transcripts.

| S-EPMC5601920 | biostudies-literature

Aberrant metabolic processes promote the immunosuppressive microenvironment in multiple myeloma.

Project description:IntroductionMultiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood.MethodsIn this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis.ResultsWe found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy.DiscussionIn summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

| S-EPMC9748558 | biostudies-literature

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