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CRISPR-Cas9 screen identify IGF2BP1 as a top, essential MYCN-synergizing candidate in the 17q-gain region

ABSTRACT: To systemically identify potential, crucial gene(s) in 17q-gain that contribute to MYCN-amplified neuroblastoma, we conducted an unbiased CRISPR-based negative selection screen from 17q21-ter locus genes in MYCN-amp/17q-gain neuroblastoma NLF cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE333426 | GEO | 2026/05/31

REPOSITORIES: GEO

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IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression [human sWGS]

Project description:Chromosome 17q gain is an independent prognostic marker in neuroblastoma, harboring several potential oncogenes including IGF2BP1 and BIRC5. IGF2BP1 was shown to be upregulated in unfavorable neuroblastoma and correlates with poor patient survival. Here, we report that overexpression of IGF2BP1 in a transgenic mouse model induces neuroblastoma with all characteristics known for human neuroblastoma, including MYCN upregulation and genomic aberrations. Furthermore, we demonstrate that genes located at chromosome 17q have an exceptionally high potential as therapeutic targets in addition to a combined inhibition of IGF2BP1 and BIRC5 resulting in additive effects.

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IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression [mouse sWGS]

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IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression [human RNA-seq]

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IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression [mouse miRNA-Seq]

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IGF2BP1 in 17q-gain cooperates with MYCN to regulate purine biosynthesis and immunotherapy efficacy in neuroblastoma

Project description:Concurrent chromosomal 17q-gain and MYCN amplification define a subset of neuroblastoma associated with particularly adverse clinical outcomes. However, how these genetic alterations synergize to promote tumor progression and whether their cooperation confers therapeutic vulnerabilities remain elusive. We herein performed a CRISPR-based functional screen targeting 17q-gain genes and identified the RNA m6A reader IGF2BP1 as a critical MYCN collaborator to promote aggressive neuroblastomas via activation of PAICS, a key enzyme involved in de novo purine biosynthesis. Rewiring of PAICS-mediated nucleotide metabolism enabled tumor cells to sustain necessary purine pools for productive transcription of replicative stress-responsive genes, including CHK1, to cope with the exacerbated replication stress. Pharmacological inhibition of CHK1 elicited a robust immune reprogramming, leading to activation of cGAS-STING signaling, upregulation of MHC-I expression and synergistic tumor suppression with immune checkpoint blockade. Altogether, we identify an IGF2BP1/MYCN-PAICS-CHK1 axis that drives aggressive neuroblastoma phenotypes and constitutes an actionable vulnerability for therapeutic intervention.

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CRISPR-Cas9 screen identify IGF2BP1 as a top, essential MYCN-synergizing candidate in the 17q-gain region

Project description:CRISPR-Cas9 screen identify IGF2BP1 as a top, essential MYCN-synergizing candidate in the 17q-gain region

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Project description:To achieve the very high oncoprotein levels required to drive the malignant state, cancer cells utilise the ubiquitin proteasome system to regulate proteins involved in growth signalling pathways. Here we identify a transcriptional coactivator, ALYREF, expressed from the most common genetic copy number variation in childhood neuroblastoma, chromosome 17q21-ter gain. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. MYCN induced ALYREF transcription, and the two proteins formed a nuclear coactivator complex which stimulated transcription of the ubiquitin specific peptidase 3, USP3. We found that increased USP3 levels markedly reduced K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF was required for MYCN effects on the malignant phenotype in vitro and that of USP3 on MYCN stability. Our data define a novel MYCN oncoprotein dependency state which provides rationale for future pharmacological studies.

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IGF2BP1 in 17q-gain cooperates with MYCN to regulate purine biosynthesis and immunotherapy efficacy in neuroblastoma

Project description:IGF2BP1 in 17q-gain cooperates with MYCN to regulate purine biosynthesis and immunotherapy efficacy in neuroblastoma

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