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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 the alternative nonhomologous end joining 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 cell viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1 inhibition were correlated with an increase of DNA double-strand breaks, activation of the DNA damage response and apoptosis. Importantly, by comparing a gene expression signature of PARP-inhibitor sensitivity to our plasma cell dyscrasia gene expression profiling, we identified a subset of MM patients who could benefit from PARP inhibitors. In particular, gene set enrichment analysis suggested that high MYC expression correlates with sensitivity to PARP inhibitors in MM. Indeed, we identified MYC as a promoter of PARP1-mediated repair in MM and, consistently, we demonstrated that cytotoxic effects induced by PARP inhibition are mostly detectable in MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 alternative non-homologous end joining repair, which therefore represents a druggable target in this still incurable disease.

Original languageEnglish
Pages (from-to)185-195
Number of pages11
JournalHaematologica
Volume106
Issue number1
DOIs
Publication statusPublished - Jan 2021

ASJC Scopus subject areas

  • Hematology

Fingerprint

Dive into the research topics of 'Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma'. Together they form a unique fingerprint.

Cite this