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<p>Chromosome copy number variations are poorly understood drivers of human malignancies. −7/del(7q) is common in acute myeloid leukemia, confers a poor prognosis, and is thought to harbor several tumor suppressors. Previously, we identified the histone methyltransferase <i>KMT2C</i> as a tumor suppressor in this region. Here, through a differentiation CRISPR screen in hematopoietic stem and progenitor cells, we find that the mitochondrial iron transporter ABCB8 is essential for their differentiation. <i>ABCB8</i> deficiency accelerates leukemogenesis in vivo and disrupts iron homeostasis, reducing cytoplasmic iron availability and impairing iron-dependent enzymes, including the histone demethylase KDM6A. Consequently, <i>ABCB8</i> loss elevates H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner. Notably, <i>ABCB8</i> and <i>KMT2C</i>, neighboring genes on 7q, cooperatively regulate H3K27me3 to suppress leukemogenesis. Our findings reveal <i>ABCB8</i> as a tumor suppressor in −7/del(7q) acute myeloid leukemia and uncover an epigenetic collaboration between neighboring tumor suppressors, driven by iron-mediated chromatin remodeling.</p>

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Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to −7/del(7q) leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Jianan Zheng,
  • Yiman Peng,
  • Xintong Deng,
  • Lanxin Zhang,
  • Zhongwang Wang,
  • Xuelan Chen,
  • He Li,
  • Yanxin Li,
  • Qi Zhang,
  • Liuxian Zheng,
  • Ziyi Qi,
  • Lan Wang,
  • Min Lu,
  • Wenguo Cui,
  • Li Wang,
  • Yu Wu,
  • Weili Zhao,
  • Ting Niu,
  • Chong Chen,
  • Yu Liu

摘要

Chromosome copy number variations are poorly understood drivers of human malignancies. −7/del(7q) is common in acute myeloid leukemia, confers a poor prognosis, and is thought to harbor several tumor suppressors. Previously, we identified the histone methyltransferase KMT2C as a tumor suppressor in this region. Here, through a differentiation CRISPR screen in hematopoietic stem and progenitor cells, we find that the mitochondrial iron transporter ABCB8 is essential for their differentiation. ABCB8 deficiency accelerates leukemogenesis in vivo and disrupts iron homeostasis, reducing cytoplasmic iron availability and impairing iron-dependent enzymes, including the histone demethylase KDM6A. Consequently, ABCB8 loss elevates H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner. Notably, ABCB8 and KMT2C, neighboring genes on 7q, cooperatively regulate H3K27me3 to suppress leukemogenesis. Our findings reveal ABCB8 as a tumor suppressor in −7/del(7q) acute myeloid leukemia and uncover an epigenetic collaboration between neighboring tumor suppressors, driven by iron-mediated chromatin remodeling.