Authors

Silvia Maifrede, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Bac Viet Le, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Nencki Institute of Experimental Biology, Warsaw, Poland
Margaret Nieborowska-Skorska, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Konstantin Golovine, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Katherine Sullivan-Reed, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Wangisa M B Dunuwille, Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri
Joseph Nacson, Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Michael Hulse, Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Kelsey Keith, Coriell Institute for Medical Research, Camden, New Jersey
Jozef Madzo, Coriell Institute for Medical Research, Camden, New Jersey
Lisa Beatrice Caruso, Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Zachary Gazze, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Zhaorui Lian, Coriell Institute for Medical Research, Camden, New Jersey
Antonella Padella, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola, Italy
Kumaraswamy N. Chitrala, Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Boris A. Bartholdy, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
Ksenia Matlawska-Wasowska, Division of Hematology-Oncology, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Daniela Di Marcantonio, Research Institute of Fox Chase Cancer Center, Immune Cell Development and Host Defense, Philadelphia, Pennsylvania
Giorgia Simonetti, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola, Italy
Georg Greiner, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
Stephen M Sykes, Research Institute of Fox Chase Cancer Center, Immune Cell Development and Host Defense, Philadelphia, Pennsylvania
Peter Valent, Division of Hematology and Hemostaseology and Ludwig-Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
Elisabeth M. Paietta, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, New York
Martin S. Tallman, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York
Hugo F. Fernandez, Moffitt Malignant Hematology and Cellular Therapy at Memorial Healthcare System, Pembroke Pines, Florida
Mark R. Litzow, Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
Mark D. Minden, Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada
Jian Huang, Coriell Institute for Medical Research, Camden, New Jersey
Giovanni Martinelli, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola, Italy
George S. Vassiliou, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Italo Tempera, Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Katarzyna Piwocka, Nencki Institute of Experimental Biology, Warsaw, Poland
Neil Johnson, Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Grant A. Challen, Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri
Tomasz Skorski, Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania

Document Type

Article

Publication Date

10-1-2021

Abstract

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F , and MPLW515L , or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52 . Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2-Wilms' tumor 1 (WT1)-binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. SIGNIFICANCE: TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase-positive malignant hematopoietic cells to PARP inhibitors.

Publisher

American Association for Cancer Research

Publication Title

Cancer research

ISSN

1538-7445

Volume

81

Issue

19

First Page

5089

Last Page

5101

DOI

10.1158/0008-5472.CAN-20-3761

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