FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia
Open accessAbstract
Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.
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Upregulation of HDAC8 during FLT3 therapy is mediated by FOXP2 and FOXP3.
“Upregulation of HDAC8 during FLT3 therapy is mediated by TFs FOXP2 and FOXP3 (Long et al., 2020).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Long et al., 2020
This resistance depends on HDAC8 deacetylase activity against TP53.
“This resistance depends on the deacetylase activity of HDAC8 against TP53 described above.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Long et al., 2020
HDAC8 is upregulated after quizartinib treatment in AML.
“Here, HDAC8 is upregulated after treatment with quizartinib, an inhibitor of FMS-like receptor tyrosine kinase 3 (FLT3).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Long et al., 2020
Combination of quizartinib with HDAC8 inhibitor 22d greatly reduces AML cell survival.
“The combination of quizartinib with the HDAC8 inhibitor 22d (Fig. 3), greatly reduces AML cell survival.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Long et al., 2020
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References 51 · Cited by 84
- Authors
- Long, J., Jia, M.-Y., Fang, W.-Y., Chen, X.-J., Mu, L.-L., Wang, Z.-Y., Shen, Y., Xiang, R.-F., Wang, L.-N., Wang, L., Jiang, C.-H., Jiang, J.-L., Zhang, W.-J., Sun, Y.-D., Chang, L., Gao, W.-H., Wang, Y., Li, J.-M., Hong, D.-L., Liang, A.-B., & Hu, J.
- Affiliations
- Tongji University (CN)
- Blood and Marrow Transplantation Center, Department of Hematology, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China;
- Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao-Tong University School of Medicine, Shanghai, China; and
- Shanghai Jiao Tong University (CN)
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China;
- Corresponding author
- Long, Jun
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2020-04-23
- Volume
- 135
- Issue
- 17
- Pages
- 1472-1483
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W3006597436
- Cited by
- 84
- References
- 51
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 18 · 2021: 11 · 2020: 5
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81730007, 2017YFA0104502, 81830004, 31872842, 81770151, 81770187, 81920108005)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- FLT3-ITD, acute myeloid leukemia, FLT3 inhibitors, HDAC8, p53 inactivation, FOXO1, FOXO3, histone deacetylation, drug resistance, leukemia maintenance, AC220, combination therapy, patient-derived xenografts, tyrosine kinase mutations
- MeSH terms
- Forkhead Box Protein O1, Animals, Histone Deacetylases, Humans, Mutation, Prognosis, Repressor Proteins, Tumor Cells, Cultured, Biomarkers, Tumor, Leukemia, Myeloid, Acute, Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Mice, SCID, Mice, Inbred NOD, Apoptosis, Drug Resistance, Neoplasm, Tandem Repeat Sequences, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Cell Proliferation, Mice, fms-Like Tyrosine Kinase 3
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