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The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia (scRNA-Seq)

ABSTRACT: Mutation of TP53, a tumor suppressor in cancer, is common and leads to extremely poor prognosis. To identify vulnerabilities in TP53-mutated tumors, we performed genome-wide CRISPR/Cas9 screens using isogenic Trp53 wild-type and knockout mouse acute myeloid leukemia (AML) lines. Here, we show that histone gene regulation governed by the XPO7-NPAT pathway is essential for survival of TP53-mutated AML cells. In TP53 wild-type cells, XPO7 enhances p53 nuclear localization and functions as a tumor suppressor, but in TP53-mutated cells, XPO7 promotes cell proliferation by retaining NPAT, a histone gene activator, in the nucleus. NPAT depletion led to genome-wide histone loss, enhancing vulnerability to genotoxic stress. Human AML cases show predominant expression of XPO7 and NPAT when TP53 is mutated, suggesting a potential therapeutic vulnerability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264596 | GEO | 2026/02/09

REPOSITORIES: GEO

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Project description:Background: TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers. Methods: Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through In vitro and in vivo experiments, we explored proliferation, transformation potential, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis. Results: Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability. Conclusions: PRJNA1092607Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.

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The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia (scRNA-Seq)

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