BATF promotes extramedullary infiltration through TGF-β1/Smad/MMPs axis in acute myeloid leukemia

Mol Carcinog. 2024 Jun;63(6):1146-1159. doi: 10.1002/mc.23715. Epub 2024 Mar 13.

Abstract

Acute myeloid leukemia (AML) is one of the most prevalent types of leukemia and is challenging to cure for most patients. Basic Leucine Zipper ATF-Like Transcription Factor (BATF) has been reported to participate in the development and progression of numerous tumors. However, its role in AML is largely unknown. In this study, the expression and prognostic value of BATF were examined in AML. Our results demonstrated that BATF expression was upregulated in AML patients, which was significantly correlated with poor clinical characteristics and survival. Afterward, functional experiments were performed after knocking down or overexpressing BATF by transfecting small interfering RNAs and overexpression plasmids into AML cells. Our findings revealed that BATF promoted the migratory and invasive abilities of AML cells in vitro and in vivo. Moreover, the target genes of BATF were searched from databases to explore the binding of BATF to the target gene using ChIP and luciferase assays. Notably, our observations validated that BATF is bound to the promoter region of TGF-β1, which could transcriptionally enhance the expression of TGF-β1 and activate the TGF-β1/Smad/MMPs signaling pathway. In summary, our study established the aberrantly high expression of BATF and its pro-migratory function via the TGF-β1-Smad2/3-MMP2/9 axis in AML, which provides novel insights into extramedullary infiltration of AML.

Keywords: BATF; MMPs; TGF‐β1; acute myeloid leukemia; extramedullary infiltration; migration.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors* / genetics
  • Basic-Leucine Zipper Transcription Factors* / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Male
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Middle Aged
  • Neoplasm Invasiveness
  • Prognosis
  • Signal Transduction
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1* / genetics
  • Transforming Growth Factor beta1* / metabolism

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Smad Proteins
  • Transforming Growth Factor beta1
  • BATF protein, human