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Effect of PBX1 overexpression in PCM6 and MM1S myeloma cell lines

ABSTRACT: Effect of PBX1 overexpression in PCM6 and MM1S myeloma cell lines

PROVIDER: PRJNA1069674 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27742946_1.fastq.gz	Fastqsanger.gz
	SRR27742946_2.fastq.gz	Fastqsanger.gz
	SRR27742947_1.fastq.gz	Fastqsanger.gz
	SRR27742947_2.fastq.gz	Fastqsanger.gz
	SRR27742948_1.fastq.gz	Fastqsanger.gz

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Systems medicine dissection of chromosome 1q amplification reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Project description:Here we report the use of high-throughput sequencing technologies (RNA-seq, ChIP-seq) to identify the molecular programme of PBX1 and FOXM1 in multiple myeloma cells (MM1S, U266 cell lines). We performed Chromatin Immunoprecipitation followed by sequencing (ChIP-seq) against PBX1 in MM1S and U266 cells (n=2). In addition, we identifed the transcriptome of PBX1-depleted and FOXM1-depleted myeloma cells 3 days after transduction with shRNA-expressing lentiviral vectors. Molecular characterization revealed PBX1 as a novel epigenetic regulator of myeloma cell survival and proliferation. PBX1 directly and unilaterally controls the FOXM1 transcriptional programme and, together,they regulate the high-risk transcriptional signature of chr1q-amplified cells. Pharmacological inhibition of the unified PBX1-FOXM1 axis with thiostrepton showed selectivity against chr1q-amplified MM. Altogether, these data reveal PBX1-FOXM1 axis as a novel therapeutic avenue against chr1q-amplified MM.

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Effect of PBX1 overexpression in PCM6 and MM1S myeloma cell lines

Project description:Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers have been identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and has already been studied using RNA-seq. In this study a massive (325,025 cells and 49 patients) single cell multiomic dataset was generated with jointly quantified ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identified an association between one plasma cell subtype with myeloma progression that we have called relapsed/refractory plasma cells (RRPCs). These cells are associated with 1q alterations, TP53 mutations, and higher expression of PHF19. We also identified downstream regulation of cell cycle inhibitors in these cells, possible regulation of the transcription factor (TF) PBX1 on 1q, and determined that PHF19 may be acting primarily through this subset of cells.

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