TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.

Autor:	Maifrede S; Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Le BV; 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., Nieborowska-Skorska M; Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Golovine K; Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Sullivan-Reed K; Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Dunuwille WMB; Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri., Nacson J; Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Hulse M; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Keith K; Coriell Institute for Medical Research, Camden, New Jersey., Madzo J; Coriell Institute for Medical Research, Camden, New Jersey., Caruso LB; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Gazze Z; Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Lian Z; Coriell Institute for Medical Research, Camden, New Jersey., Padella A; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori,' Meldola, Italy., Chitrala KN; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Bartholdy BA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York., Matlawska-Wasowska K; Division of Hematology-Oncology, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico., Di Marcantonio D; Research Institute of Fox Chase Cancer Center, Immune Cell Development and Host Defense, Philadelphia, Pennsylvania., Simonetti G; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori,' Meldola, Italy., Greiner G; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Sykes SM; Research Institute of Fox Chase Cancer Center, Immune Cell Development and Host Defense, Philadelphia, Pennsylvania., Valent P; Division of Hematology and Hemostaseology and Ludwig-Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria., Paietta EM; Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, New York., Tallman MS; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Fernandez HF; Moffitt Malignant Hematology and Cellular Therapy at Memorial Healthcare System, Pembroke Pines, Florida., Litzow MR; Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota., Minden MD; Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada., Huang J; Coriell Institute for Medical Research, Camden, New Jersey., Martinelli G; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori,' Meldola, Italy., Vassiliou GS; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom., Tempera I; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Piwocka K; Nencki Institute of Experimental Biology, Warsaw, Poland., Johnson N; Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Challen GA; Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri. tskorski@temple.edu grantchallen@wustl.edu., Skorski T; Fels Cancer Institute for Personalized Medicine and Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania. tskorski@temple.edu grantchallen@wustl.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Oct 01; Vol. 81 (19), pp. 5089-5101. Date of Electronic Publication: 2021 Jul 02.
DOI:	10.1158/0008-5472.CAN-20-3761
Abstrakt:	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 FLT3 ITD , BCR-ABL1, JAK2 V617F , and MPL W515L , or with mutations affecting related signaling pathways such as NRAS G12D and CALR del52 . 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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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