Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors
Kenta Yamamoto,
Jiguang Wang,
Lisa Sprinzen,
Jun Xu,
Christopher J Haddock,
Chen Li,
Brian J Lee,
Denis G Loredan,
Wenxia Jiang,
Alessandro Vindigni,
Dong Wang,
Raul Rabadan,
Shan Zha
Affiliations
Kenta Yamamoto
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States; Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States
Jiguang Wang
Department of Biomedical Informatics, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States; College of Physicians & Surgeons, Columbia University, New York, United States
Lisa Sprinzen
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States; Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States
Jun Xu
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States
Christopher J Haddock
Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States
Chen Li
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States
Brian J Lee
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States
Denis G Loredan
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States
Wenxia Jiang
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States
Alessandro Vindigni
Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States
Dong Wang
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States
Raul Rabadan
Department of Biomedical Informatics, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States; College of Physicians & Surgeons, Columbia University, New York, United States
Institute for Cancer Genetics, Columbia Unviersity, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States; College of Physicians and Surgeons, Columbia University, New York, United States; Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Columbia University, New York, United States; Department of Pediatrics, Columbia University, New York, United States; College of Physicians & Surgeons, Columbia University, New York, United States
Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.
