ArticleScientific reports2022
Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 16 citations in OpenAlex.
- Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death inHemaSphere · 2026Article
- Dual-functional Nanocarrier for Improved Immunochemotherapy of Acute Myeloid Leukemia.Research square · 2026Article
- Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.Cell death discovery · 2026Article
- CHK1 as a Metabolic and Immunological Regulator: Implications for Cancer Therapy.Oncology research · 2026Review
- Targeting nucleotide metabolism and epigenetic regulation to overcome the differentiation blockade in AML.Leukemia research reports · 2026Review
- Unraveling skeletal muscle senescence in anFrontiers in aging · 2026Article
- Unlocking nature's potential: Soursop in the battle against resistant acute myeloid leukemia.Biochemistry and biophysics reports · 2025Review
- Identification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.Angewandte Chemie (International ed. in English) · 2025Article
- Review
- Article
- Bone marrow stromal cells enhance differentiation of acute myeloid leukemia induced by pyrimidine synthesis inhibitors.American journal of physiology. Cell physiology · 2024Article
- The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.Blood advances · 2024Article
- Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia.JCI insight · 2024Article
- Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations.International journal of molecular sciences · 2023Article
- Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia.Frontiers in pharmacology · 2023Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation therapy of AML so that several new drugs have been proposed, including inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis. Cytarabine, a backbone of standard AML therapy, is known to induce differentiation at low doses, but the mechanism is not completely elucidated. We have previously reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) and brequinar, a DHODH inhibitor, induced differentiation of myeloid leukemia by activating the ataxia telangiectasia and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) via pyrimidine depletion. In this study, using immunoblotting, flow cytometry analyses, pharmacologic inhibitors and genetic inactivation of Chk1 in myeloid leukemia cell lines, we show that low dose cytarabine induces differentiation by activating Chk1. In addition, cytarabine induces differentiation ex vivo in a subset of primary AML samples that are sensitive to AICAr and DHODH inhibitor. The results of our study suggest that leukemic cell differentiation stimulated by low doses of cytarabine depends on the activation of Chk1 and thus shares the same pathway as pyrimidine synthesis inhibitors.
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