TY - JOUR
T1 - Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma
AU - Caracciolo, D.
AU - Scionti, F.
AU - Juli, G.
AU - Altomare, E.
AU - Golino, G.
AU - Todoerti, K.
AU - Grillone, K.
AU - Riillo, C.
AU - Arbitrio, M.
AU - Iannone, M.
AU - Morelli, E.
AU - Amodio, N.
AU - Di Martino, M. T.
AU - Rossi, Marco
AU - Neri, Alessio
AU - Tagliaferri, P.
AU - Tassone, P.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - n/a
KW - n/a
UR - http://hdl.handle.net/10807/306244
U2 - 10.3324/haematol.2019.240713
DO - 10.3324/haematol.2019.240713
M3 - Article
SN - 0390-6078
VL - 106
SP - 185
EP - 195
JO - Haematologica
JF - Haematologica
ER -