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Nucleophosmin sustains WNT-driven cell proliferation and tumor initiation in vivo

ABSTRACT: Nucleophosmin (NPM1) is a nucleolar protein frequently overexpressed in many solid tumours with little known about its functional role to support carcinogenesis. Here, we identify Npm1 as a commonly upregulated gene following Apc loss in highly proliferative tissues, and high expression correlates with increased proliferation in CRC patients. We show that NPM1 is dispensable for adult epithelial tissue homeostasis, however, it has a profound effect on WNT-driven intestinal and liver tumourigenesis, leading to reduced proliferation and extension of survival. Mechanistically, NPM1 depletion triggers integrated stress response (ISR) and p53 pathway activation. P53 deletion, or inhibition of the ISR effects, rescue proliferation following NPM1 loss. Overall, our results demonstrate that NPM1 supports WNT-driven cell proliferation and tumour initiation by attenuating p53 pathway activation or induction of ISR. Being dispensable for homeostasis, NPM1 presents as a promising target for cancer therapy in WNT-driven tumours with functional p53, including difficult to treat KRAS-mutant CRC and hepatic cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE249958 | GEO | 2024/02/15

REPOSITORIES: GEO

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Project description:Background: MicroRNAs are regulators of gene expression, mainly functioning by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To further illuminate the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation, we performed an integrative analysis of microRNA and mRNA expression data sets. Design and Methods: Both microRNA and gene expression profiles were measured in a cohort of 43 adult acute myeloid leukemia patient samples (n=42 cytogenetically normal, n=1 del7q; median age 46 years [range 23-60]) of known NPM1 mutation status (n=23 mutated, n=20 wild-type) and data integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative RT-PCR, Western Blot and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays. Results: Our integrative approach of analyzing both microRNA and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA - target mRNA interactions, we could identify and validate 77 novel candidates with known or potential implication in leukemogenesis, such as IRF2-miR-20a, KIT-miR-20a and MN1-miR-15a. Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs such as miR-29a and miR-30c might contribute to the sensitivity to cytarabine, which is observed in NPM1-mutated acute myeloid leukemia. Conclusions: Overall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA - target gene interactions of potential relevance for acute myeloid leukemia treatment. MicroRNA and gene expression profiles were measured in a cohort of 43 adult (42 cytogenetically normal and 1 del7q) acute myeloid leukemia patient samples of known NPM1 mutation status (n=23 mutated, n=20 wild-type). This submission represents the mRNA expression component of the study. The miRNA expression data will be deposited as supplementary information along with the accompanying manuscript.

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Nucleophosmin sustains WNT-driven cell proliferation and tumor initiation in vivo

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