ABSTRACT
RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer. SIGNIFICANCE: Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription-replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.
Subject(s)
Leukemia , Spliceosomes , Humans , Spliceosomes/genetics , R-Loop Structures , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , DNA Repair , Leukemia/drug therapy , Leukemia/genetics , RNA Splicing Factors/genetics , Poly (ADP-Ribose) Polymerase-1/geneticsABSTRACT
Clinical imaging research is a fast-growing, complex, and integral part of drug and therapy discovery and development. Research sponsors rely on outside vendors to manage their trials and deliver results they hope will demonstrate the efficacy of their product. Specialized vendors known as imaging contract research organizations have teams of highly trained and specialized professionals who lend their expertise to all aspects of imaging research management, of which nuclear medicine technologists are key team members. This article is part of the Clinical Trials Network Research Series for Technologists and will help provide an overview of an imaging research study from initiation to data delivery and the roles that nuclear medicine technologists and other imaging professionals play.
