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

ABSTRACT: Chromosome copy number variations (CNVs) are among the most critical yet poorly understood genetic drivers of human malignancies. -7/del(7q) is one of the most common CNVs in acute myeloid leukemia (AML) and is associated with poor prognosis. It has been proposed that there might be multiple tumor suppressor genes (TSGs) in these CNVs. Previously, we identified KMT2C, a histone methyltransferase, as a tumor suppressor gene in chromosome 7q. In this study, we performed a differentiation CRISPR screening of hematopoietic stem and progenitor cells (HSPCs) and discovered that ABCB8, encoding a mitochondrial iron transporter, is essential for HSPC differentiation. ABCB8 deficiency accelerated leukemogenesis in vivo and disrupted iron homeostasis, reducing cytoplasmic iron availability and impairing iron-dependent enzymes, including the histone demethylase KDM6A. Consequently, ABCB8 loss elevated H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner. Notably, ABCB8 and KMT2C, neighboring genes on 7q, cooperatively regulated H3K27me3 to suppress leukemogenesis. Our findings reveal ABCB8 as a novel TSG in -7/del(7q) AML and uncover an unprecedented epigenetic collaboration between neighboring TSGs, driven by iron-mediated chromatin remodeling.

ORGANISM(S): Mus musculus

PROVIDER: GSE294258 | GEO | 2026/04/21

REPOSITORIES: GEO

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