Zhiyan Silvia Liu, Sayantani Sinha, Maxwell Bannister, Axia Song, Erica Arriaga-Gomez, Alexander J McKeeken, Elizabeth A Bonner, Benjamin K Hanson, Martina Sarchi, Kouhei Takashima, Dawei Zong, Victor M Corral, Evan Nguyen, Jennifer Yoo, Wannasiri Chiraphapphaiboon, Cassandra Leibson, Matthew C McMahon, Sumit Rai, Elizabeth M Swisher, Zohar Sachs, Srinivas Chatla, Derek L Stirewalt, H Joachim Deeg, Tomasz Skorski, Eirini P Papapetrou, Matthew J Walter, Timothy A Graubert, Sergei Doulatov, Stanley C Lee, Hai Dang Nguyen
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...
November 15, 2023: Cancer Research