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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168948 | GEO | 2022/03/13

REPOSITORIES: GEO

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Project description:Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of plasma cells (PCs) in the bone marrow (BM). The genetic background and clinical course of the disease are largely heterogeneous, and MM pathophysiology ranges from the premalignant condition of monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM, symptomatic MM, and extramedullary MM/plasma cell leukemia (PCL). Recent genome-wide sequencing efforts have provided the rationale for molecularly aimed treatment approaches, identifying mutations that can be specifically targeted, such as those in the mitogen-activated protein kinase (MAPK) pathway, which represent the most prevalent mutations in MM. Among these, mutations affecting BRAF gene, detected in 4-15% of patients, are of potential immediate clinical relevance due to the availability of effective inhibitors of this serine-threonine kinase which are in fact being explored also in myeloma. In this study, we screened by next generation sequencing (NGS) a large and representative series of intramedullary and extramedullary MM patients, including primary and secondary plasma cell leukemia (pPCL and sPCL, respectively), for mutations in BRAF, NRAS and KRAS genes. We evaluated the relationship of identified variants with other clinical and biological features and determined the transcriptional signature associated with MAPK pathway activation in MM. To further elucidate the transcriptional programs modulated by BRAF activation in MM, we used the PLX4032 drug to inhibit BRAF activity in U266 human myeloma cell line (HMCL), carrying K601N mutation and showing constitutive activation of MEK/ERK signaling. After confirming its ability to suppress MAPK pathway and myeloma cell proliferation in culture in the U266 cell line, we investigated the specific modulation of gene expression induced by the drug. U266 cells were treated with PLX4032 (30 µM) or DMSO for 12 hours and subjected to gene expression profiling (GEP) analysis by using Affymetrix GeneChip Human Gene 1.0ST arrays.

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

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