Biomaterial Database

Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma. 2021

Daniele Caracciolo, and Francesca Scionti, and Giada Juli, and Emanuela Altomare, and Gaetanina Golino, and Katia Todoerti, and Katia Grillone, and Caterina Riillo, and Mariamena Arbitrio, and Michelangelo Iannone, and Eugenio Morelli, and Nicola Amodio, and Maria Teresa Di Martino, and Marco Rossi, and Antonino Neri, and Pierosandro Tagliaferri, and Pierfrancesco Tassone

Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.

Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. Since we previously demonstrated that LIG3-dependent repair is involved in the genomic instability, drug resistance and survival of MM cells, we here investigated the biological relevance of PARP1, a driver component of Alternative-Non Homologous End Joining (Alt-NHEJ) pathway, in MM. We found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by Olaparib impaired MM cells viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1-inhibition were correlated to increase of DNA double-strand breaks, activation of DNA Damage Response (DDR) and finally apoptosis. Importantly, by comparing a gene expression signature of PARP inhibitors (PARPi) sensitivity to our plasma cell dyscrasia (PC) gene expression profiling (GEP), we identified a subset of MM patients which could benefit from PARP inhibitors. In particular, Gene Set Enrichment Analysis (GSEA) suggested that high MYC expression correlates to PARPi sensitivity in MM. Indeed, we identified MYC as promoter of PARP1-mediated repair in MM and, consistently, we demonstrate that cytotoxic effects induced by PARP inhibition are mostly detectable on MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 Alt-NHEJ repair, which represents therefore a druggable target in this still incurable disease.

UI	MeSH Term	Description	Entries
D009101	Multiple Myeloma	A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.	Myeloma, Plasma-Cell,Kahler Disease,Myeloma, Multiple,Myeloma-Multiple,Myelomatosis,Plasma Cell Myeloma,Cell Myeloma, Plasma,Cell Myelomas, Plasma,Disease, Kahler,Multiple Myelomas,Myeloma Multiple,Myeloma, Plasma Cell,Myeloma-Multiples,Myelomas, Multiple,Myelomas, Plasma Cell,Myelomas, Plasma-Cell,Myelomatoses,Plasma Cell Myelomas,Plasma-Cell Myeloma,Plasma-Cell Myelomas
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D017209	Apoptosis	A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.	Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D042822	Genomic Instability	An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.	Genome Instability,Genome Stability,Genomic Stability,Genome Instabilities,Genome Stabilities,Genomic Instabilities,Genomic Stabilities,Instabilities, Genome,Instabilities, Genomic,Instability, Genome,Instability, Genomic,Stabilities, Genome,Stabilities, Genomic,Stability, Genome,Stability, Genomic
D045744	Cell Line, Tumor	A cell line derived from cultured tumor cells.	Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D053903	DNA Breaks, Double-Stranded	Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.	Double-Stranded DNA Breaks,Double-Strand DNA Breaks,Double-Stranded DNA Break,Break, Double-Strand DNA,Break, Double-Stranded DNA,Breaks, Double-Strand DNA,Breaks, Double-Stranded DNA,DNA Break, Double-Strand,DNA Break, Double-Stranded,DNA Breaks, Double Stranded,DNA Breaks, Double-Strand,Double Strand DNA Breaks,Double Stranded DNA Break,Double Stranded DNA Breaks,Double-Strand DNA Break
D059766	DNA End-Joining Repair	The repair of DOUBLE-STRAND DNA BREAKS by rejoining the broken ends of DNA to each other directly.	Non-Homologous DNA End-Joining,End-Joining DNA Repair,MMEJ DNA Repair,Microhomology-Mediated End Joining Repair,NHEJ DNA Repair,Nonhomologous DNA End-Joining,DNA End Joining Repair,DNA End-Joining, Non-Homologous,DNA End-Joining, Nonhomologous,DNA Repair, End-Joining,DNA Repair, MMEJ,DNA Repair, NHEJ,End Joining DNA Repair,End-Joining Repair, DNA,End-Joining, Non-Homologous DNA,Microhomology Mediated End Joining Repair,Non Homologous DNA End Joining,Nonhomologous DNA End Joining,Repair, DNA End-Joining,Repair, End-Joining DNA,Repair, MMEJ DNA,Repair, NHEJ DNA

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