c-JUN interacts with HDAC1 as a potential combinatorial therapeutic target in acute myeloid leukemia

Ke Wu; Xiaoyu Xu; Wei Wei; Jie Wen; Haixi Hu

doi:10.1016/j.intimp.2024.113927

c-JUN interacts with HDAC1 as a potential combinatorial therapeutic target in acute myeloid leukemia

Int Immunopharmacol. 2024 Dec 24:146:113927. doi: 10.1016/j.intimp.2024.113927. Online ahead of print.

Authors

Ke Wu¹, Xiaoyu Xu², Wei Wei³, Jie Wen⁴, Haixi Hu⁵

Affiliations

¹ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
² Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
³ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: weiweill@ustc.edu.cn.
⁴ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: jiewen@ustc.edu.cn.
⁵ Department of Scientific Research, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China. Electronic address: irishu@ustc.edu.cn.

PMID: 39721452
DOI: 10.1016/j.intimp.2024.113927

Abstract

Acute myeloid leukemia (AML) is a biologically heterogeneous disease originating from the clonal expansion of hematopoietic stem cells (HSCs). Clonal expansion of hematopoietic stem cell progenitors (HSC-Prog), along with a block in differentiation, are hallmark features of AML. The disease is characterized by poor clinical outcomes, highlighting the urgent need for effective therapeutic strategies and suitable drug targets. We conducted multi-omics analyses, including single-cell RNA sequencing (scRNA-seq), Mendelian randomization (MR), and bulk RNA-seq, to investigate HDAC1's oncogenic role in AML. We identified specific gene signatures at the single-cell level. MR with eQTL data established causal links, and TCGA-LAML RNA-seq provided prognostic insights. Analysis of cellular communication and transcription factors revealed high c-JUN activity in HSC-Prog. We confirmed the association of c-JUN with HDAC1 through Western blotting and Co-immunoprecipitation (Co-IP). Functional validation of c-JUN in AML cells was performed via flow cytometry in vitro. The effectiveness of drugs targeting c-JUN and HDAC1 was assessed in mouse models using live imaging methods like in vivo imaging system (IVIS) and iSMAART. We identified the activity of c-JUN is specifically enhanced in HSC-Prog in AML patients. We suggest a potential regulatory relationship between c-JUN and HDAC1 in AML tumor cells. Inhibition of c-JUN can suppress cell proliferation and CD33 expression in AML, enhancing susceptibility to natural killer (NK) cell-mediated cytotoxicity. The combination of agents targeting c-JUN (Ailanthone) and HDAC1 (Panobinostat) showed robust efficacy in treating AML in xenograft mouse models, outperforming monotherapy. We also observed that the combination of Ailanthone and Panobinostat therapy displayed a safe pharmacological profile without dose-dependent toxicity, suggesting its potential as a therapeutic strategy.

Keywords: Acute myeloid leukemia; Combination therapy; HDAC1; Mendelian randomization; Single cell RNA-seq; c-JUN.