Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer
Abstract
Abstract Loss-of-function (LoF) mutations frequently found in human cancers are generally intractable by classical small molecule inhibitor approaches. Among them are mutations affecting Polycomb-group (PcG) epigenetic regulators, enhancer of zeste homolog 2 (EZH2) and Additional sex combs like 1 (ASXL1), frequently found in hematological malignancies of myeloid or lymphoid lineage, and their concurrent mutations associates with particularly poor prognosis. Although there is a clear need to develop novel and effective treatments for these patients, the lack of appropriate disease models and mechanistic insights have significantly hindered the progress. Here, we show that genetic inactivation of Asxl1 and Ezh2 in murine hematopoietic stem/progenitor cells results in highly penetrant hematological malignancies as observed in corresponding human diseases. These PcG proteins regulate both coding and noncoding genomes, leading to marked reactivation of transposable elements (TEs) and DNA damage responses in PcG LoF–mutated cells, which create a novel vulnerability for poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi)–induced synthetic lethality. Using both mouse models and primary patient samples, we demonstrate that Asxl1/Ezh2-mutated cells are highly sensitive to PARPis that induce excessive DNA damage and significantly extend disease latency. Intriguingly, the observed PARPi sensitivity can be specifically overridden by reverse transcriptase inhibitors that interrupt target site–primed reverse transcription and life cycle of TEs. This mechanism is contrastingly different from the current concept of BRCAness associated PARPi-induced synthetic lethality, which largely rely on deficient homologous recombination, and is independent on reverse transcriptase inhibitors. Together, this study reveals a novel application and mechanism of PARPi-induced synthetic lethal targeting of blood cancers with reactivated TEs such as those carrying PcG epigenetic mutations.
Article Details
Authors (24)
Bernd B. Zeisig
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Chiou-Tsun Tsai
Clemence Virely
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Tsz Kan Fung
1King's College London, Comprehensive Cancer Center, London, United Kingdom
Ali Tuğrul Akin
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Estelle Troadec
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Bo Jiao
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
I. Richard Thompson
Priscilla Nga Ieng Lau
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Nanjun Li
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Andriani Charalambous
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Larissa Bomfim
1King's College London, Comprehensive Cancer Center, London, United Kingdom
Jennifer Lynch
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Athina Georgiou
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Robbert Hoogeboom
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Claire Lynn
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Si-Yi Zhang
Hunan Provincial Key Laboratory of Flexible Electronic Materials Genome Engineering, School of Physics and Electronic Science, Changsha University of Science and Technology 1 , Changsha 410114,
Piers E. M. Patten
7Department of Haematology, Comprehensive Cancer Centre, King’s College London, London, United Kingdom
Cynthia L. Fisher
5School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
Anna Schuh
Seishi Ogawa
Ghulam Mufti
43King's College, London, United Kingdom
Mohammad M. Karimi
Chi Wai Eric So
1Comprehensive Cancer Centre, King’s College London, London, United Kingdom