Science and Research

IRF2BP2 counteracts the ATF7/JDP2 AP-1 heterodimer to prevent inflammatory overactivation in acute myeloid leukemia (AML) cells

Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.

  • Fischer, S.
  • Weber, L. M.
  • Stielow, B.
  • Frech, M.
  • Simon, C.
  • Geller, M.
  • Könnecke, J.
  • Finkernagel, F.
  • Forné, I.
  • Nist, A.
  • Bauer, U. M.
  • Stiewe, T.
  • Neubauer, A.
  • Liefke, R.

Keywords

  • Humans
  • *Leukemia, Myeloid, Acute/genetics/metabolism/pathology
  • *Transcription Factor AP-1/metabolism/genetics
  • *Inflammation/genetics/metabolism
  • Cell Line, Tumor
  • Activating Transcription Factors/metabolism/genetics
  • Chromatin/metabolism
  • Cell Proliferation
  • Repressor Proteins/metabolism/genetics
  • HEK293 Cells
  • Gene Expression Regulation, Leukemic
  • Protein Multimerization
  • Transcription Factors/metabolism/genetics
  • DNA-Binding Proteins
Publication details
DOI: 10.1093/nar/gkae437
Journal: Nucleic Acids Res
Pages: 7590-7609 
Number: 13
Work Type: Original
Location: UGMLC
Disease Area: LC, PALI
Partner / Member: UMR
Access-Number: 38801077

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