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<p>Cell-intrinsic repression of inflammatory signaling supports the survival of acute myeloid leukemia blasts. However, how the cell-intrinsic inflammation status changes during AML progression remains elusive. Here, we used CRISPR-mediated genome editing to create a murine AML model driven by a chromosomal translocation between the <i>mixed-lineage leukemia</i> (<i>Mll</i>) gene and the <i>Mllt3/Af9</i> gene. The resulting MLL-AF9 (MA9) fusion protein is sufficient to immortalize hematopoietic stem and progenitor cells (HSPCs) in vitro but insufficient to induce an overt leukemia phenotype in vivo rapidly. Leukemia progression in vivo is associated with a downregulation of type I interferon response genes, and this process depends on the upregulation of MA9 transcriptional target <i>Pbx3</i> in the progenitor cell compartment. Accordingly, enhancing interferon response by interferon-α (IFNα) administration induces leukemic cell differentiation, and inhibiting MA9 transcriptional activity on top of the enhanced IFN signaling further delays leukemia progression. Our study underscores the importance of <i>Pbx3</i>-mediated suppression of interferon response genes in the progression of MA9-induced AML and highlights the potential application of type I interferon for its treatment.</p>

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Pbx3-mediated suppression of type I interferon response contributes to leukemia progression driven by MLL-AF9

  • 期刊论文

  • 发表日期：

    2025年3月19日

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  • Li Tang,
  • Meng Lu,
  • Yulong Du,
  • Jianlong Sun

摘要

Cell-intrinsic repression of inflammatory signaling supports the survival of acute myeloid leukemia blasts. However, how the cell-intrinsic inflammation status changes during AML progression remains elusive. Here, we used CRISPR-mediated genome editing to create a murine AML model driven by a chromosomal translocation between the mixed-lineage leukemia (Mll) gene and the Mllt3/Af9 gene. The resulting MLL-AF9 (MA9) fusion protein is sufficient to immortalize hematopoietic stem and progenitor cells (HSPCs) in vitro but insufficient to induce an overt leukemia phenotype in vivo rapidly. Leukemia progression in vivo is associated with a downregulation of type I interferon response genes, and this process depends on the upregulation of MA9 transcriptional target Pbx3 in the progenitor cell compartment. Accordingly, enhancing interferon response by interferon-α (IFNα) administration induces leukemic cell differentiation, and inhibiting MA9 transcriptional activity on top of the enhanced IFN signaling further delays leukemia progression. Our study underscores the importance of Pbx3-mediated suppression of interferon response genes in the progression of MA9-induced AML and highlights the potential application of type I interferon for its treatment.