细胞内铁稳态调控的表观遗传重编程促进-7/del(7q)白血病
Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia.
摘要(中文译文)
染色体拷贝数变异是人类恶性肿瘤中研究不足的驱动因素。-7/del(7q)在急性髓系白血病中常见，提示预后不良，并被认为携带多个抑癌基因。此前，我们在该区域鉴定出组蛋白甲基转移酶KMT2C为抑癌基因。本研究通过造血干/祖细胞中的分化CRISPR筛选，发现线粒体铁转运蛋白ABCB8对其分化至关重要。ABCB8缺陷在体内加速白血病发生，并破坏铁稳态，降低细胞质铁可利用性，损害铁依赖性酶，包括组蛋白去甲基化酶KDM6A。因此，ABCB8缺失升高H3K27me3水平，以铁和KDM6A依赖的方式抑制分化基因。值得注意的是，ABCB8与KMT2C作为7q上的相邻基因，协同调控H3K27me3以抑制白血病发生。我们的研究揭示ABCB8是-7/del(7q)急性髓系白血病中的抑癌基因，并揭示了相邻抑癌基因之间由铁介导的染色质重塑所驱动的表观遗传协同作用。
Abstract
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.
如何引用
AMA
Jianan Zheng, Yiman Peng, Xintong Deng, Lanxin Zhang, Zhongwang Wang, Xuelan Chen, et al. Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia.. Nature communications. 2026; doi:10.1038/s41467-026-75292-2.
APA
Jianan Zheng, Yiman Peng, Xintong Deng, Lanxin Zhang, Zhongwang Wang, Xuelan Chen, et al (2026). Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia.. Nature communications. https://doi.org/10.1038/s41467-026-75292-2
GB/T 7714
Jianan Zheng, Yiman Peng, Xintong Deng, Lanxin Zhang, Zhongwang Wang, Xuelan Chen, et al. Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75292-2.
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