2. Academic Validation
  3. Single-cell profiling-guided combination therapy of c-Fos and histone deacetylase inhibitors in diffuse large B-cell lymphoma

Single-cell profiling-guided combination therapy of c-Fos and histone deacetylase inhibitors in diffuse large B-cell lymphoma

  • Clin Transl Med. 2022 May;12(5):e798. doi: 10.1002/ctm2.798.
Luqiao Wang 1 2 3,  Zijuan Wu 1 2 3,  Yi Xia 1 2 3,  Xueying Lu 1 2 3,  Ji Li 4,  Lei Fan 1 2 3,  Chun Qiao 1 2 3,  Hairong Qiu 1 2 3,  Danling Gu 1 2 3,  Wei Xu 1 2 3,  Jianyong Li 1 2 3 5,  Hui Jin 1 2 3
Affiliations

Affiliations

  • 1 Department of Hematology, Pukou CLL Center, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
  • 2 Key Laboratory of Hematology of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
  • 3 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China.
  • 4 Singleron Biotechnologies, Nanjing, China.
  • 5 National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China.
PMID: 35522945 DOI: 10.1002/ctm2.798
Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Histone deacetylase inhibitors (HDACis) have been widely applied in multiple tumours, but the expected efficacy was not observed in DLBCL. Therefore, this study is aimed to explore superior HDACis and optimise a relative combinational therapeutic strategy.

Methods: The antitumour effects of the drug were evaluated by Cell Counting Kit-8 (CCK-8) assay and Apoptosis analysis. Single-cell RNA sequencing (scRNA-Seq) was used to analyse the intratumoural heterogeneity of DLBCL cells. Whole-exome sequencing and RNA sequencing were performed to analyse the genetic and transcriptional features. Western blotting, qRT-PCR, protein array, immunohistochemistry, and chromatin immunoprecipitation assays were applied to explore the involved pathways. The antitumour effects of the compounds were assessed using subcutaneous xenograft tumour models.

Results: LAQ824 was screened and confirmed to kill DLBCL cells effectively. Using scRNA-Seq, we characterised the heterogeneity of DLBCL cells under different drug pressures, and c-Fos was identified as a critical factor in the survival of residual tumour cells. Moreover, we demonstrated that combinatorial treatment with LAQ824 and a c-Fos inhibitor more potently inhibited tumour cells both in vitro and in vivo.

Conclusion: Altogether, we found an HDACi, LAQ824, with high efficacy in DLBCL and provided a promising HDACi-based combination therapy strategy.

Keywords

combination treatment; diffuse large B-cell lymphoma; histone deacetylase inhibitor; single-cell RNA sequencing.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12270
    99.59%, c-Fos/AP-1 Inhibitor