ArticleLeukemia2020
Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells (HSPCs) with TOP1-targeted drugs and PARP1 inhibitors.
Article in Leukemia, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 19 citations in OpenAlex.
- A cross platform m7G risk score based on five gene pairs stratifies prognosis and stemness in acute myeloid leukemia.Discover oncology · 2026Article
- Current Understanding of CHIP's Immunobiological Footprint with A Focus on Gastrointestinal Disorders: A Review of the Literature.Current oncology reports · 2026Review
- Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- TET2 mutation in acute myeloid leukemia: biology, clinical significance, and therapeutic insights.Clinical epigenetics · 2024Review
- Characterization of stem cell landscape and assessing the stemness degree to aid clinical therapeutics in hematologic malignancies.Scientific reports · 2024Article
- Clonal Hematopoiesis: Updates and Implications at the Solid Tumor-Immune Interface.JCO precision oncology · 2023Review
- Synthetic lethal targeting of TET2-mutant haematopoietic stem and progenitor cells by XPO1 inhibitors.British journal of haematology · 2023Article
- Transcriptomic Analysis of CRISPR/Cas9-Mediated PARP1-Knockout Cells under the Influence of Topotecan and TDP1 Inhibitor.International journal of molecular sciences · 2023Article
- Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia.Cell reports · 2023Article
- Depletion ofFrontiers in hematology · 2023Article
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- TET2: A cornerstone in normal and malignant hematopoiesis.Cancer science · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inactivating mutations in TET2 serve as an initiating genetic lesion in the transformation of hematopoietic stem and progenitor cells (HSPCs). Thus, effective therapy for this subset of patients would ideally include drugs that are selectively lethal in TET2-mutant HSPCs, at dosages that spare normal HSPCs. In this study, we tested 129 FDA-approved anticancer drugs in a tet2-deficient zebrafish model and showed that topoisomerase 1 (TOP1)-targeted drugs and PARP1 inhibitors selectively kill tet2-mutant HSPCs. We found that Tet2-deficient murine bone marrow progenitors and CRISPR-Cas9-induced TET2-mutant human AML cells were more sensitive to both classes of drugs compared with matched control cells. The mechanism underlying the selective killing of TET2-mutant blood cells by these drugs was due to aberrantly low levels of tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that is important for removing TOP1 cleavage complexes (TOP1cc). Low TDP1 levels yield sensitivity to TOP1-targeted drugs or PARP1 inhibitors and an inability to remove TOP1 cleavage complexes, leading to DNA double-strand breaks and cell death. The finding that TET2 mutations render HSPCs uniquely vulnerable to disruption of TOP1 and PARP1 activity may therefore represent a unique opportunity to use relatively low dosages of these drugs for the "precision therapy" of TET2-mutant myeloid malignancies.
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