Year: 2023
Type: article
Abstract: 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.
Source: Cell Reports
Authors: 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
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: American Cancer Society, V Foundation for Cancer Research, New York State Department of Health, Leukemia and Lymphoma Society, University of Miami, Vera and Joseph Dresner Foundation, National Institutes of Health, Leonard M. Miller School of Medicine, Miami Clinical and Translational Science Institute, University of Miami, National Cancer Institute
OpenAlex ID: W4317810035