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Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation [U-937 ATAC-Seq]

GSE241583 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 8 samples Submitted 2025/09/30 Platform GPL24676
Summary
Enhancing TET2 activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective epigenetic reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces RARA-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human AML models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
Published in
Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation
Leesang TE, Brabson JP, Yap YS et al. · Cell reports 2025 · PMID 41037397 · doi:10.1016/j.celrep.2025.116379
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Also filed as BioProject PRJNA1008738 and SRA study SRP456775. Searching any of these in the dataset finder brings you back here.

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