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Ref Type Journal Article
PMID (34215619)
Authors Maifrede S, Le BV, Nieborowska-Skorska M, Golovine K, Sullivan-Reed K, Dunuwille WMB, Nacson J, Hulse M, Keith K, Madzo J, Caruso LB, Gazze Z, Lian Z, Padella A, Chitrala KN, Bartholdy BA, Matlawska-Wasowska K, Di Marcantonio D, Simonetti G, Greiner G, Sykes SM, Valent P, Paietta EM, Tallman MS, Fernandez HF, Litzow MR, Minden MD, Huang J, Martinelli G, Vassiliou GS, Tempera I, Piwocka K, Johnson N, Challen GA, Skorski T
Title TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 81 19 2021 10 01 5089-5101 Cancer Res
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
DNMT3A loss TET2 loss acute myeloid leukemia sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) inhibited colony formation in murine acute myeloid leukemia cells harboring TET2 and DNMT3A loss along wtih various oncogenic tyrosine kinase mutations in culture (PMID: 34215619). 34215619
DNMT3A del acute myeloid leukemia resistant Olaparib Preclinical - Cell culture Actionable In a preclinical study, mouse acute myeloid leukemia cells harboring a DNMT3A deletion along with FLT3-ITD mutation were resistant to Lynparza (olaparib) in culture (PMID: 34215619). 34215619
DNMT3A loss TET2 loss acute myeloid leukemia sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) decreased colony formation in murine acute myeloid leukemia cells harboring TET2 and DNMT3A loss along with a FLT3-ITD mutation in culture (PMID: 34215619). 34215619
FLT3 exon 14 ins TET2 loss acute myeloid leukemia sensitive Doxorubicin + Olaparib + Quizartinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib), Adriamycin (doxorubicin), and Vanflyta (quizartinib) increased DNA double-strand breaks and decreased colony formation in mouse acute myeloid leukemia cells harboring a FLT3-ITD mutation and TET2 loss in culture (PMID: 34215619). 34215619
DNMT3A loss FLT3 exon 14 ins TET2 loss acute myeloid leukemia sensitive Quizartinib + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Vanflyta (quizartinib) and Talzenna (talazoparib) decreased colony formation in mouse acute myeloid leukemia cells harboring a FLT3-ITD mutation and TET2 and DNMT3A loss in culture (PMID: 34215619). 34215619
DNMT3A loss FLT3 exon 14 ins TET2 loss acute myeloid leukemia sensitive Doxorubicin + Olaparib + Quizartinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib), Adriamycin (doxorubicin), and Vanflyta (quizartinib) increased DNA double-strand breaks and decreased colony formation in mouse acute myeloid leukemia cells harboring a FLT3-ITD mutation and TET2 and DNMT3A loss in culture (PMID: 34215619). 34215619
DNMT3A loss FLT3 exon 14 ins acute myeloid leukemia no benefit Quizartinib + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, the addition of Talzenna (talazaparib) did not enhance the sensitivity of mouse acute myeloid leukemia cells harboring a FLT3-ITD mutation and DNMT3A loss to Vanflyta (quizartinib) treatment compared to Vanflyta (quizartinib) alone in culture (PMID: 34215619). 34215619
JAK2 V617F TET2 loss acute myeloid leukemia sensitive Olaparib + Rituximab Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Lynparza (olaparib) and Rituxan (rituximab) decreased colony formation in mouse acute myeloid leukemia cells harboring JAK2 V617F and TET2 loss in culture (PMID: 34215619). 34215619
TET2 loss acute myeloid leukemia sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) inhibited colony formation in mouse acute myeloid leukemia cells harboring TET2 loss along with various oncogenic tyrosine kinase mutations in culture (PMID: 34215619). 34215619
DNMT3A del TET2 del acute myeloid leukemia sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) inhibited colony formation of mouse acute myeloid leukemia cells harboring TET2 and DNMT3A deletion along with a FLT3-ITD mutation in culture (PMID: 34215619). 34215619
DNMT3A loss acute myeloid leukemia resistant Olaparib Preclinical - Cell culture Actionable In a preclinical study, mouse acute myeloid leukemia cells harboring DNMT3A loss along with various oncogenic tyrosine kinase mutations were resistant to Lynparza (olaparib) in culture (PMID: 34215619). 34215619
FLT3 exon 14 ins TET2 loss acute myeloid leukemia sensitive Olaparib + Quizartinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib) and Vanflyta (quizartinib) decreased colony formation in murine acute myeloid leukemia cells harboring a FLT3-ITD mutation and TET2 loss in culture (PMID: 34215619). 34215619
DNMT3A mut FLT3 exon 14 ins TET2 mut acute myeloid leukemia sensitive Doxorubicin + Olaparib + Quizartinib Preclinical - Patient cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib), Adriamycin (doxorubicin), and Vanflyta (quizartinib) inhibited colony formation in patient-derived acute myeloid leukemia cells harboring FLT3-ITD and DNMT3A and TET2 mutations along with an NPM1 mutation in culture (PMID: 34215619). 34215619
JAK2 V617F TET2 loss acute myeloid leukemia sensitive Hydroxyurea + Olaparib + Rituximab Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib), Droxia (hydroxyurea), and Rituxan (rituximab) combination treatment decreased colony formation in mouse acute myeloid leukemia cells harboring JAK2 V617F and TET2 loss in culture (PMID: 34215619). 34215619
FLT3 exon 14 ins TET2 mut acute myeloid leukemia sensitive Doxorubicin + Olaparib + Quizartinib Preclinical - Patient cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib), Adriamycin (doxorubicin), and Vanflyta (quizartinib) inhibited colony formation in patient-derived acute myeloid leukemia cells harboring FLT3-ITD and a TET2 mutation along with an NPM1 mutation in culture (PMID: 34215619). 34215619
DNMT3A mut FLT3 exon 14 ins TET2 mut acute myeloid leukemia sensitive Olaparib + Quizartinib Preclinical - Patient cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib) and Vanflyta (quizartinib) inhibited colony formation in patient-derived acute myeloid leukemia cells harboring FLT3-ITD and DNMT3A and TET2 mutations along with an NPM1 mutation in culture (PMID: 34215619). 34215619
TET2 loss acute myeloid leukemia sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) decreased colony formation in mouse acute myeloid leukemia cells harboring TET2 loss along with a FLT3-ITD mutation in culture (PMID: 34215619). 34215619
TET2 A1505T TET2 mut acute myeloid leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited colony formation of patient-derived acute myeloid leukemia cells harboring FLT3-ITD and a TET2 mutation along with an NPM1 mutation and expressing TET2 A1505T in culture (PMID: 34215619). 34215619
TET2 mutant acute myeloid leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited colony formation in patient-derived acute myeloid leukemia cells harboring a TET2 mutation along with FLT3-ITD and NPM1 mutation in culture (PMID: 34215619). 34215619
DNMT3A mut TET2 mut acute myeloid leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited colony formation in patient-derived acute myeloid leukemia cells co-harboring a DNMT3A and TET2 mutation along with FLT3-ITD and NPM1 mutation in culture (PMID: 34215619). 34215619
TET2 del acute myeloid leukemia sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) inhibited colony formation of mouse acute myeloid leukemia cells harboring TET2 deletion along with a FLT3-ITD mutation in culture (PMID: 34215619). 34215619
FLT3 exon 14 ins TET2 mut acute myeloid leukemia sensitive Olaparib + Quizartinib Preclinical - Patient cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib) and Vanflyta (quizartinib) inhibited colony formation in patient-derived acute myeloid leukemia cells harboring FLT3-ITD and a TET2 mutation along with an NPM1 mutation in culture (PMID: 34215619). 34215619
DNMT3A loss acute myeloid leukemia resistant Talazoparib Preclinical - Cell culture Actionable In a preclinical study, mouse acute myeloid leukmia cells harboring DNMT3A loss along with a FLT3-ITD mutation were resistant to Talzenna (talazoparib) in culture (PMID: 34215619). 34215619
DNMT3A mutant acute myeloid leukemia resistant Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived acute myeloid leukemia cells harboring a DNMT3A mutation along with FLT3-ITD and NPM1 mutation were resistant to Lynparza (olaparib) in culture (PMID: 34215619). 34215619
DNMT3A loss FLT3 exon 14 ins TET2 loss acute myeloid leukemia sensitive Olaparib + Quizartinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib) and Vanflyta (quizartinib) decreased colony formation in mouse acute myeloid leukemia cells harboring a FLT3-ITD mutation and TET2 and DNMT3A loss in culture (PMID: 34215619). 34215619
FLT3 exon 14 ins TET2 loss acute myeloid leukemia sensitive Quizartinib + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Vanflyta (quizartinib) and Talzenna (talazoparib) decreased colony formation in mouse acute myeloid leukemia cells harboring a FLT3-ITD mutation and TET2 loss in culture (PMID: 34215619). 34215619