Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia

  • Cell Rep. 2023 Jan 31;42(1):112027. doi: 10.1016/j.celrep.2023.112027.
John P Brabson  1 ,  Tiffany Leesang  1 ,  Yoon Sing Yap  1 ,  Jingjing Wang  2 ,  Minh Q Lam  1 ,  Byron Fang  1 ,  Igor Dolgalev  2 ,  Daniela A Barbieri  3 ,  Victoria Strippoli  1 ,  Carolina P Bañuelos  4 ,  Sofia Mohammad  1 ,  Peter Lyon  5 ,  Sana Chaudhry  5 ,  Dane Donich  1 ,  Anna Swirski  1 ,  Evan Roberts  5 ,  Ivelisse Diaz  5 ,  Daniel Karl  6 ,  Helena Gomes Dos Santos  3 ,  Ramin Shiekhattar  3 ,  Benjamin G Neel  7 ,  Stephen D Nimer  8 ,  Ramiro E Verdun  6 ,  Daniel Bilbao  9 ,  Maria E Figueroa  10 ,  Luisa Cimmino  11
Affiliations
  • 1. Department 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.
  • 2. Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA.
  • 3. 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, USA.
  • 4. Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
  • 5. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
  • 6. 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, USA.
  • 7. Laura 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, USA.
  • 8. Department 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, USA.
  • 9. Sylvester 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, USA.
  • 10. Department 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, USA.
  • 11. Department 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. Electronic address: [email protected].
PMID: 36848231 DOI: 10.1016/j.celrep.2023.112027
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.

Keywords
CP: Cancer; PARPi; ascorbate; leukemia; oxidized methylcytosine; tet2.
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