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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]

ABSTRACT: TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with AML. Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via BER that slows leukemia progression. We utilized genetic and compound library screening approaches to identify rational combination treatment strategies to improve the use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several FDA approved drugs, vitamin C treatment with PARPi elicited a strong synergistic effect at blocking AML self-renewal in murine and human AML models. Vitamin C-mediated TET activation combined with PARPi caused an enrichment of chromatin-bound PARP1 at oxidized mCs, and H2AX accumulation during mid-S phase leading to cell-cycle stalling and differentiation. Given most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.

ORGANISM(S): Mus musculus

PROVIDER: GSE217586 | GEO | 2022/11/12

REPOSITORIES: GEO

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Project description:Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytsosine (5fC), and 5-carboxylcytosine (5caC). 5fC/5caC can be excised and repaired by the base excision repair (BER) pathway, implicating 5mC oxidation in active DNA demethylation. Genome-wide DNA methylation is erased in the transition from metastable states to ground state of embryonic stem cells (ESCs) and in migrating primordial germ cells (PGCs), while some resistant regions become demethylated only in gonadal PGCs. Understanding the mechanisms underlying global hypomethylation in naïve ESCs and developing PGCs will be useful for realizing cellular pluripotency and totipotency. In this study, we found that PRDM14, the PR-domain-containing transcriptional regulator, accelerates the TET-BER cycle, resulting in the promotion of active DNA demethylation in ESCs. Induction of PRDM14 expression rapidly removed the 5mC associated with transient elevation of 5hmC at pluripotency-associated genes, germline-specific genes, and imprinted loci but not across the entire genome, which resemble second wave of DNA demethylation in gonadal PGCs. PRDM14 physically interacts with TET1/TET2 and enhances the recruitment of TET1/TET2 at target loci. Knockdown of Tet1/Tet2 impaired transcriptional regulation and DNA demethylation by PRDM14. The repression of the BER pathway by administration of pharmacological inhibitors against APE1 and PARP1 and the knockdown of thymine DNA glycosylase (TDG) also impaired DNA demethylation by PRDM14. Furthermore, DNA demethylation induced by PRDM14 normally takes place in the presence of aphidicolin, which is an inhibitor of G1/S progression. Together, our analysis provides mechanistic insight into DNA demethylation in naive pluripotent stem cells and developing PGCs. To investigate the function of TET1/TET2 in transcriptional regulation by PRDM14 in ESCs, we exploited microarray analysis using total mRNA derived from Scramble, Scramble + PRDM14, Tet1/Tet2 KD, Tet1/Tet2 KD + PRDM14 mouse ESC.

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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]

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