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Mitochondria iron transporter ABCB8 contributes to -7/del(7q) leukemia through regulating histone methylation

ABSTRACT: Chromosome deletions are common in human cancers and often correlate with poor prognosis. Tumor suppressor genes are enriched in these deleted regions, yet their functional roles remain understudied, as their alterations typically involve copy number loss rather than mutations. Focusing on the commonly deleted 7q36 region in myeloid malignancies, we performed an sgRNA library screen and identified candidate genes whose loss disrupts hematopoietic stem and progenitor cell (HSPC) differentiation. Among these, ABCB8, encoding a mitochondrial iron transporter, was found to promote acute myeloid leukemia (AML) progression when combined with Trp53 and Nf1 loss. Mechanistically, ABCB8 deficiency impairs iron-dependent histone demethylase KDM6A activity, leading to differentiation blockade. Iron supplementation partially rescued this defect. Notably, KMT2C, another 7q36-located TSG and core COMPASS-like complex component, cooperated with ABCB8 loss to exacerbate differentiation arrest and leukemogenesis. Strikingly, ABCB8-deficient or del(7q) leukemia cells were vulnerable to ABCB8 restoration or EZH2 inhibition, suggesting therapeutic strategies. Our study uncovers a link between mitochondrial iron homeostasis, epigenetic regulation, and 7q deletion-driven leukemogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE294258 | GEO | 2025/04/14

REPOSITORIES: GEO

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