ArticleArchives of toxicology2022
Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3.
Article in Archives of toxicology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 26 citations in OpenAlex.
- Current Research in Polypharmacology for Cancer Treatment Using Dual-Target Histone Deacetylase Inhibitors.International journal of molecular sciences · 2026Review
- Recent Advances in FLT3-Based Dual Inhibitors: A Promising Strategy for the Treatment of Acute Myeloid Leukemia.Current medicinal chemistry · 2026Review
- Review
- The deacetylases HDAC1/HDAC2 control JAK2Signal transduction and targeted therapy · 2025Article
- The epigenetic revolution in hematology: from benchside breakthroughs to clinical transformations.Clinical and experimental medicine · 2025Review
- Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.Cell death discovery · 2025Article
- Histone deacetylase inhibitors for leukemia treatment: current status and future directions.European journal of medical research · 2024Review
- Selective inhibition of HDAC class IIA as therapeutic intervention for KMT2A-rearranged acute lymphoblastic leukemia.Communications biology · 2024Article
- Development of Epigenetic Modifiers with Therapeutic Potential in FMS-Related Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Acute Myeloid Leukemia and Other Blood Malignancies.ACS pharmacology & translational science · 2024Article
- Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells.Journal of advanced research · 2024Article
- Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition.Oncogene · 2022Article
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase (FLT3) is a clinically unresolved problem. AML cells frequently have a dysregulated expression and activity of epigenetic modulators of the histone deacetylase (HDAC) family. Therefore, we tested whether a combined inhibition of mutant FLT3 and class I HDACs is effective against AML cells. Low nanomolar doses of the FLT3 inhibitor (FLT3i) AC220 and an inhibition of class I HDACs with nanomolar concentrations of FK228 or micromolar doses of the HDAC3 specific agent RGFP966 synergistically induce apoptosis of AML cells that carry hyperactive FLT3 with an internal tandem duplication (FLT3-ITD). This does not occur in leukemic cells with wild-type FLT3 and without FLT3, suggesting a preferential toxicity of this combination against cells with mutant FLT3. Moreover, nanomolar doses of the new FLT3i marbotinib combine favorably with FK228 against leukemic cells with FLT3-ITD. The combinatorial treatments potentiated their suppressive effects on the tyrosine phosphorylation and stability of FLT3-ITD and its downstream signaling to the kinases ERK1/ERK2 and the inducible transcription factor STAT5. The beneficial pro-apoptotic effects of FLT3i and HDACi against leukemic cells with mutant FLT3 are associated with dose- and drug-dependent alterations of cell cycle distribution and DNA damage. This is linked to a modulation of the tumor-suppressive transcription factor p53 and its target cyclin-dependent kinase inhibitor p21. While HDACi induce p21, AC220 suppresses the expression of p53 and p21. Furthermore, we show that both FLT3-ITD and class I HDAC activity promote the expression of the checkpoint kinases CHK1 and WEE1, thymidylate synthase, and the DNA repair protein RAD51 in leukemic cells. A genetic depletion of HDAC3 attenuates the expression of such proteins. Thus, class I HDACs and hyperactive FLT3 appear to be valid targets in AML cells with mutant FLT3.
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