Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia
Summary: TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723000384 |
| _version_ | 1797944969060679680 |
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| author | John P. Brabson Tiffany Leesang Yoon Sing Yap Jingjing Wang Minh Q. Lam Byron Fang Igor Dolgalev Daniela A. Barbieri Victoria Strippoli Carolina P. Bañuelos Sofia Mohammad Peter Lyon Sana Chaudhry Dane Donich Anna Swirski Evan Roberts Ivelisse Diaz Daniel Karl Helena Gomes Dos Santos Ramin Shiekhattar Benjamin G. Neel Stephen D. Nimer Ramiro E. Verdun Daniel Bilbao Maria E. Figueroa Luisa Cimmino |
| author_facet | John P. Brabson Tiffany Leesang Yoon Sing Yap Jingjing Wang Minh Q. Lam Byron Fang Igor Dolgalev Daniela A. Barbieri Victoria Strippoli Carolina P. Bañuelos Sofia Mohammad Peter Lyon Sana Chaudhry Dane Donich Anna Swirski Evan Roberts Ivelisse Diaz Daniel Karl Helena Gomes Dos Santos Ramin Shiekhattar Benjamin G. Neel Stephen D. Nimer Ramiro E. Verdun Daniel Bilbao Maria E. Figueroa Luisa Cimmino |
| author_sort | John P. Brabson |
| collection | DOAJ |
| description | Summary: TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant. |
| first_indexed | 2024-04-10T20:47:58Z |
| format | Article |
| id | doaj.art-5e49692c1c5545df90f0bdb82844b32f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T20:47:58Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-5e49692c1c5545df90f0bdb82844b32f2023-01-24T04:07:30ZengElsevierCell Reports2211-12472023-01-01421112027Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemiaJohn P. Brabson0Tiffany Leesang1Yoon Sing Yap2Jingjing Wang3Minh Q. Lam4Byron Fang5Igor Dolgalev6Daniela A. Barbieri7Victoria Strippoli8Carolina P. Bañuelos9Sofia Mohammad10Peter Lyon11Sana Chaudhry12Dane Donich13Anna Swirski14Evan Roberts15Ivelisse Diaz16Daniel Karl17Helena Gomes Dos Santos18Ramin Shiekhattar19Benjamin G. Neel20Stephen D. Nimer21Ramiro E. Verdun22Daniel Bilbao23Maria E. Figueroa24Luisa Cimmino25Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USALaura and Isaac Perlmutter Cancer Center and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USASylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Corresponding authorSummary: TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.http://www.sciencedirect.com/science/article/pii/S2211124723000384CP: Cancer |
| spellingShingle | John P. Brabson Tiffany Leesang Yoon Sing Yap Jingjing Wang Minh Q. Lam Byron Fang Igor Dolgalev Daniela A. Barbieri Victoria Strippoli Carolina P. Bañuelos Sofia Mohammad Peter Lyon Sana Chaudhry Dane Donich Anna Swirski Evan Roberts Ivelisse Diaz Daniel Karl Helena Gomes Dos Santos Ramin Shiekhattar Benjamin G. Neel Stephen D. Nimer Ramiro E. Verdun Daniel Bilbao Maria E. Figueroa Luisa Cimmino Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia Cell Reports CP: Cancer |
| title | Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia |
| title_full | Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia |
| title_fullStr | Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia |
| title_full_unstemmed | Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia |
| title_short | Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia |
| title_sort | oxidized mc modulates synthetic lethality to parp inhibitors for the treatment of leukemia |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723000384 |
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