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Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα

Cell Death & Differentiation volume 30, pages 1320–1333 (2023)Cite this article

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Abstract

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RARα. Mechanistically, we found that HDAC3 deacetylated PML-RARα at lysine 394, which reduced PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RARα ubiquitylation and degradation and reduced the expression of PML-RARα in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.

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Fig. 1: HDAC3 is highly expressed in the APL subtype, and inhibition of HDAC3 suppresses APL progression by inducing apoptosis and differentiation of APL cells.
Fig. 2: Inhibition of HDAC3 suppresses APL progression and produces a synergistic effect with ATRA.
Fig. 3: Inhibition of HDAC3 induces PML-RARα degradation by enhancing ubiquitination.
Fig. 4: HDAC3-mediated PML-RARα deacetylation interferes with PML-RARα ubiquitination and degradation.
Fig. 5: Inhibition of HDAC3 induces differentiation and apoptosis in drug-resistant APL cells by degrading PML-RARα mutations.
Fig. 6: Inhibition of HDAC3 relieves APL in animal models inoculated with drug-resistant APL cells.
Fig. 7: Schematic diagram illustrating the mechanism by which APL is relieved through HDAC3 inhibition.

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Data availability

The dataset analyzed during this study can be accessed using the GEO with accession GSE13204. All the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Key R&D Program of China (2022YFA1106100), the National Natural Science Foundation of China (81770187, 82170149, 82222070, 82273973, 81872904, 82073887, 82073711 and 82003798), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-030, 2022-I2M-2-002 to KL; 2021-I2M-1-070 to TTZ) and the Fundamental Research Funds for the Central Universities (2022-RC350-07, 3332022149).

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Author notes

  1. These authors contributed equally: Bo Dai, Feng Wang, Ying Wang.

Authors and Affiliations

  1. Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Rd, Shanghai, 200025, China

    Bo Dai, Ying Wang, Jiayan Zhu, Lining Wang, Wenhui Gao, Junmin Li & Jiong Hu

  2. NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tian Tan Xi Li, Beijing, 100050, China

    Bo Dai, Feng Wang, Yunxuan Li, Tingting Zhang, Luyao Zhao & Ke Li

  3. Department of Hematology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Bo Dai

  4. Department of Hematology, Tong Ji Hospital, Tong Ji University School of Medicine, No 389 Xincun Road, Shanghai, 200065, China

    Ying Wang

  5. Department of Hematology, The First Affiliated Hospital, College of Medicine, and Institute of Hematology, Zhejiang University, Zhejiang, 310003, China

    Honghu Zhu

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Contributions

JH, KL, BD, and FW designed the overall study and wrote the manuscript; BD and YW performed experiments and analyzed data; JZ, YL, and TZ helped with animal experiments; LZ, LW and WG helped to collect patients’ primary samples; JL and HZ provided advice and reviewed the manuscript.

Corresponding authors

Correspondence to Ke Li or Jiong Hu.

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The study was approved by the Institutional Review Board of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. All animal procedures were approved by the Institutional Committee for the Ethics of Animal Care and Treatment in Biomedical Research of Chinese Academy of Medical Sciences and PUMC.

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Dai, B., Wang, F., Wang, Y. et al. Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα. Cell Death Differ 30, 1320–1333 (2023). https://doi.org/10.1038/s41418-023-01139-8

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