Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect.

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  • Additional Information
    • Source:
      Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 8307268 Publication Model: Print Cited Medium: Internet ISSN: 1099-1069 (Electronic) Linking ISSN: 02780232 NLM ISO Abbreviation: Hematol Oncol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, England : Wiley-Blackwell, c1983-
    • Subject Terms:
      Cytarabine*/pharmacology ; Isocitrate Dehydrogenase*/genetics ; Isocitrate Dehydrogenase*/metabolism ; Leukemia, Myeloid, Acute*/genetics ; Leukemia, Myeloid, Acute*/drug therapy ; Leukemia, Myeloid, Acute*/metabolism ; Leukemia, Myeloid, Acute*/pathology ; Drug Resistance, Neoplasm* ; Mutation*; Humans ; Animals ; Mice ; Warburg Effect, Oncologic ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Cell Proliferation/drug effects ; Mice, Nude ; Glycolysis/drug effects ; Antimetabolites, Antineoplastic/pharmacology
    • Abstract:
      Mutation of isocitrate dehydrogenase 2 (IDH2) is a key factor in promoting cytarabine (Ara-C) resistance in acute myeloid leukemia (AML), however the underly mechanism remains unclear. Acute myeloid leukemia cells, were cultured with either IDH2 knockdown (KD-IDH2) or overexpression (OE-IDH2) to elucidate the role of IDH2 in these leukemic cell lines. Additionally, mutant cell lines were engineered to replicate clinically relevant IDH2 mutations. To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells. Cell proliferation was quantified using a Cell Counting Kit-8 (CCK-8), while apoptosis was evaluated through propidium iodide staining followed by flow cytometry. Glycolytic metabolism levels were measured using a specific reagent kit, and Western blotting was employed to determine the expression levels of glycolysis-related proteins. Transcriptome sequencing was conducted to elucidate the mechanisms by which IDH2 mutations influence glycolysis. Furthermore, both in vitro cell experiments and in vivo subcutaneous transplantation tumor models in nude mice were utilized to validate these mechanisms. OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.
      (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)
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    • Grant Information:
      RLMY20200020 Yunnan Province High Level Talent Training Support Program "Famous Medical Special Project"
    • Contributed Indexing:
      Keywords: AML cell; Ara‐C resistant; IDH2 mutation; Warburg effect; acute myeloid leukemia
    • Accession Number:
      04079A1RDZ (Cytarabine)
      EC 1.1.1.41 (Isocitrate Dehydrogenase)
      EC 1.1.1.41 (IDH2 protein, human)
      0 (Antimetabolites, Antineoplastic)
    • Publication Date:
      Date Created: 20241111 Date Completed: 20241111 Latest Revision: 20241128
    • Publication Date:
      20241202
    • Accession Number:
      PMC11590050
    • Accession Number:
      10.1002/hon.3316
    • Accession Number:
      39526588