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Targeting histone deacetylase 1 (HDAC1) in the bone marrow stromal cells revers imatinib resistance by modulating IL-6 in Ph + acute lymphoblastic leukemia

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Abstract

Bone marrow stromal cells (BMSCs) can promote the growth of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Histone deacetylases (HDACs) play essential roles in the proliferation and apoptosis resistance of Ph + ALL cells. In our previous study, inhibiting histone deacetylase 1 (HDAC1) decreases the proliferation of Ph + ALL cells. However, little is known regarding how HDAC1 in BMSCs of Ph + ALL patients affects the imatinib (IM) resistance. Therefore, the present work examined the roles of HDAC1 in BMSCs. Overexpression of HDAC1 was found in BMSCs of Ph + ALL patients with IM resistance. In addition, the Ph + ALL cell line SUP-B15 was co-cultured with BMSCs after lentivirus transfection for regulating HDAC1 expression. Knockdown of HDAC1 within BMSCs elevated the IM-mediated SUP-B15 cell apoptosis, while increasing HDAC1 expression had an opposite effect. IL-6 in BMSCs, which is an important factor for the microenvironment-associated chemoresistance, showed evident up-regulation in HDAC1-upregulated BMSCs and down-regulation in HDAC1-downregulated BMSCs. While recombinant IL-6 (rIL-6) can reversed the sensitivity of SUP-B15 cells to IM induced by downregulating HDAC1 expression in BMSCs. HDAC1 showed positive regulation on IL-6 transcription and secretion. Moreover, IL-6 secretion induced by HDAC1 in BMSCs might enhance IM resistance in Ph + ALL cells. With regard to the underlying molecular mechanism, NF-κB, an important signal responsible for IL-6 transcription in BMSCs, mediated the HDAC1-regulated IL-6 expression. Collectively, this study facilitated to develop HDAC1 inhibitors based not only the corresponding direct anti-Ph + ALL activity but also the regulation of bone marrow microenvironment.

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Data availability

All data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

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Funding

The present study was supported by the Science and Technology Program of Guizhou Province Health Committee (No.gzwkj2024-365).

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Authors and Affiliations

  1. Department of Pediatric Hematology, Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Guiyang, 550002, China

    Danna Wei, Xiaoling Liang, Meiling Huang, Caili Wang, Zhangmin Ye & Jingrong Zhang

  2. Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Tianzhuo Zhang

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  1. Danna Wei
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Contributions

Danna Wei, Xiaoling Liang: designed the study, completed the experiment. Meiling Huang, Caili Wang: made interpreted the data. Zhangmin Ye: prepared the manuscript for publication. Tianzhuo Zhang，Jingrong Zhang: analyzed the data and interpreted the data. All authors revised the manuscript and approved it for publication.

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Correspondence to Tianzhuo Zhang or Jingrong Zhang.

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Ethical approval was obtained from the Ethics Committee of Guiyang Maternal and Child Health Care Hospital. Guiyang Children’s Hospital.

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Wei, D., Liang, X., Huang, M. et al. Targeting histone deacetylase 1 (HDAC1) in the bone marrow stromal cells revers imatinib resistance by modulating IL-6 in Ph + acute lymphoblastic leukemia. Ann Hematol 103, 3015–3027 (2024). https://doi.org/10.1007/s00277-024-05830-9

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