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Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia
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 exc...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989506/ https://www.ncbi.nlm.nih.gov/pubmed/36848231 http://dx.doi.org/10.1016/j.celrep.2023.112027 |
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author | Brabson, John P. Leesang, Tiffany Yap, Yoon Sing Wang, Jingjing Lam, Minh Q. Fang, Byron Dolgalev, Igor Barbieri, Daniela A. Strippoli, Victoria Bañuelos, Carolina P. Mohammad, Sofia Lyon, Peter Chaudhry, Sana Donich, Dane Swirski, Anna Roberts, Evan Diaz, Ivelisse Karl, Daniel Santos, Helena Gomes Dos Shiekhattar, Ramin Neel, Benjamin G. Nimer, Stephen D. Verdun, Ramiro E. Bilbao, Daniel Figueroa, Maria E. Cimmino, Luisa |
author_facet | Brabson, John P. Leesang, Tiffany Yap, Yoon Sing Wang, Jingjing Lam, Minh Q. Fang, Byron Dolgalev, Igor Barbieri, Daniela A. Strippoli, Victoria Bañuelos, Carolina P. Mohammad, Sofia Lyon, Peter Chaudhry, Sana Donich, Dane Swirski, Anna Roberts, Evan Diaz, Ivelisse Karl, Daniel Santos, Helena Gomes Dos Shiekhattar, Ramin Neel, Benjamin G. Nimer, Stephen D. Verdun, Ramiro E. Bilbao, Daniel Figueroa, Maria E. Cimmino, Luisa |
author_sort | Brabson, John P. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9989506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-99895062023-03-07 Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia Brabson, John P. Leesang, Tiffany Yap, Yoon Sing Wang, Jingjing Lam, Minh Q. Fang, Byron Dolgalev, Igor Barbieri, Daniela A. Strippoli, Victoria Bañuelos, Carolina P. Mohammad, Sofia Lyon, Peter Chaudhry, Sana Donich, Dane Swirski, Anna Roberts, Evan Diaz, Ivelisse Karl, Daniel Santos, Helena Gomes Dos Shiekhattar, Ramin Neel, Benjamin G. Nimer, Stephen D. Verdun, Ramiro E. Bilbao, Daniel Figueroa, Maria E. Cimmino, Luisa Cell Rep Article 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. 2023-01-31 2023-01-23 /pmc/articles/PMC9989506/ /pubmed/36848231 http://dx.doi.org/10.1016/j.celrep.2023.112027 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Brabson, John P. Leesang, Tiffany Yap, Yoon Sing Wang, Jingjing Lam, Minh Q. Fang, Byron Dolgalev, Igor Barbieri, Daniela A. Strippoli, Victoria Bañuelos, Carolina P. Mohammad, Sofia Lyon, Peter Chaudhry, Sana Donich, Dane Swirski, Anna Roberts, Evan Diaz, Ivelisse Karl, Daniel Santos, Helena Gomes Dos Shiekhattar, Ramin Neel, Benjamin G. Nimer, Stephen D. Verdun, Ramiro E. Bilbao, Daniel Figueroa, Maria E. Cimmino, Luisa Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989506/ https://www.ncbi.nlm.nih.gov/pubmed/36848231 http://dx.doi.org/10.1016/j.celrep.2023.112027 |
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