TET2 and DNMT3A mutations exert divergent effects on DNA repair and sensitivity of leukemia cells to PARP inhibitors Journal Article
| Authors: | Maifrede, S.; Le, B. V.; Nieborowska-Skorska, M.; Golovine, K.; Sullivan-Reed, K.; Dunuwille, W. M. B.; Nacson, J.; Hulse, M.; Keith, K.; Madzo, J.; Caruso, L. B.; Gazze, Z.; Lian, Z.; Padella, A.; Chitrala, K. N.; Bartholdy, B. A.; Matlawska-Wasowska, K.; Di Marcantonio, D.; Simonetti, G.; Greiner, G.; Sykes, S. M.; Valent, P.; Paietta, E. M.; Tallman, M. S.; Fernandez, H. F.; Litzow, M. R.; Minden, M. D.; Huang, J.; Martinelli, G.; Vassiliou, G. S.; Tempera, I.; Piwocka, K.; Johnson, N.; Challen, G. A.; Skorski, T. |
| Article Title: | TET2 and DNMT3A mutations exert divergent effects on DNA repair and sensitivity of leukemia cells to PARP inhibitors |
| 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 DNMT3Adeficient 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. © 2021 American Association for Cancer Research |
| Keywords: | controlled study; human tissue; leukemia; unclassified drug; gene mutation; human cell; gene deletion; doxorubicin; dose response; nonhuman; animal cell; mouse; gene; homologous recombination; dna repair; gene expression; protein protein interaction; cell protein; animal experiment; animal model; in vivo study; in vitro study; drug effect; enzyme activity; brca1 protein; brca2 protein; tumor suppressor gene; regulatory mechanism; leukemia cell; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; double stranded dna break; down regulation; drug sensitivity; tet2 gene; olaparib; dna methyltransferase 3a; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; dnmt3a gene; nonhomologous end joining repair; dioxygenase; ruxolitinib; quizartinib; wt1 gene; human; article; tet2 protein; wilms tumor 1 protein; talazoparib; lig4 gene |
| Journal Title: | Cancer Research |
| Volume: | 81 |
| Issue: | 19 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-10-01 |
| Start Page: | 5089 |
| End Page: | 5101 |
| Language: | English |
| DOI: | 10.1158/0008-5472.Can-20-3761 |
| PUBMED: | 34215619 |
| PROVIDER: | scopus |
| PMCID: | PMC8487956 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
