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<p>Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by high incidence, poor prognosis, and marked genetic and clinical heterogeneity. This heterogeneity poses a significant challenge to effective treatment and underscores the urgent need for tailored therapeutic strategies. Here, we identified the EvC ciliary complex subunits EVC and EVC2 as aberrantly overexpressed in a subset of AMLs, particularly those harboring <i>ASXL1</i> mutations or the <i>t</i>(8;21) translocation, with elevated expression correlating with poor patient prognosis. Functional studies demonstrated that EVC/EVC2 are essential for maintaining the leukemogenic properties of AML cells, while being dispensable for the function of normal hematopoietic stem/progenitor cells. Loss of EVC/EVC2 impairs leukemia cell proliferation, promotes differentiation, and effectively blocks AML progression in vivo. Mechanistically, we revealed that elevated EVC/EVC2 expression is associated with gained AML1-ETO occupancy or enhanced chromatin interactions at <i>EVC/EVC2</i> promoter regions in AML cells carrying <i>t</i>(8;21) or <i>ASXL1</i> mutations, respectively. Notably, we demonstrate that the leukemogenic role of EVC/EVC2 is mediated through MYC pathway activation, independent of their canonical role in Hedgehog signaling. Collectively, our findings demonstrate an oncogenic event of overexpressed EVC/EVC2, identifying novel therapeutic vulnerabilities in AML.</p>

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Oncogenic activation of EVC/EVC2 defines a therapeutically targetable subset of acute myeloid leukemia

  • 期刊论文

  • 发表日期：

    2025年11月17日

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  • Pinpin Sui,
  • Ying Li,
  • Juyeong Hong,
  • Caroline R. Delma,
  • Shi Chen,
  • Juan Wang,
  • Peng Zhang,
  • Songmi Han,
  • Asra Noor,
  • Hui Yang,
  • Yakun Pang,
  • Yu Luan,
  • Mingjiang Xu,
  • Jihoon Lee,
  • Feng-Chun Yang

摘要

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by high incidence, poor prognosis, and marked genetic and clinical heterogeneity. This heterogeneity poses a significant challenge to effective treatment and underscores the urgent need for tailored therapeutic strategies. Here, we identified the EvC ciliary complex subunits EVC and EVC2 as aberrantly overexpressed in a subset of AMLs, particularly those harboring ASXL1 mutations or the t(8;21) translocation, with elevated expression correlating with poor patient prognosis. Functional studies demonstrated that EVC/EVC2 are essential for maintaining the leukemogenic properties of AML cells, while being dispensable for the function of normal hematopoietic stem/progenitor cells. Loss of EVC/EVC2 impairs leukemia cell proliferation, promotes differentiation, and effectively blocks AML progression in vivo. Mechanistically, we revealed that elevated EVC/EVC2 expression is associated with gained AML1-ETO occupancy or enhanced chromatin interactions at EVC/EVC2 promoter regions in AML cells carrying t(8;21) or ASXL1 mutations, respectively. Notably, we demonstrate that the leukemogenic role of EVC/EVC2 is mediated through MYC pathway activation, independent of their canonical role in Hedgehog signaling. Collectively, our findings demonstrate an oncogenic event of overexpressed EVC/EVC2, identifying novel therapeutic vulnerabilities in AML.