Half of high-risk neuroblastomas harbor MYCN amplification, and the other half overexpress C-MYC ( 10). Neuroblastoma, a malignancy of arrested development of the peripheral nervous system ( 1, 6), is a MYC-driven cancer ( 7– 9). MYC is one of the nuclear factors most often associated with dysregulated transcription, as genetic abnormalities of the MYC family of oncogenes ( C-MYC, MYCN, and MYCL1) are among the most common alterations in human cancer ( 4, 5). Our data indicate that targeting the dysregulated spliceosome by precisely inhibiting RBM39, a vulnerability in neuroblastoma, is a valid therapeutic strategy. Mechanistically, the dependency on RBM39 and high-level expression of DCAF15 determine the exquisite sensitivity of neuroblastoma to indisulam. Genetic depletion or indisulam-mediated degradation of RBM39 induces significant genome-wide splicing anomalies and cell death. Indisulam, a “molecular glue” that selectively recruits RBM39 to the CRL4-DCAF15 E3 ubiquitin ligase for proteasomal degradation, is highly efficacious against neuroblastoma, leading to significant responses in multiple high-risk disease models, without overt toxicity. Here, we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation and spliceosomal dependency, requires the splicing factor RBM39 for survival. Davidoff, and Jun Yang Show FewerĪberrant alternative pre-mRNA splicing plays a critical role in MYC-driven cancers and therefore may represent a therapeutic vulnerability. Shivendra Singh, Waise Quarni, Maria Goralski, Shibiao Wan, Hongjian Jin, Lee-Ann Van de Velde, Jie Fang, … Show All …, Qiong Wu, Ahmed Abu-Zaid, Tingting Wang, Ravi Singh, David Craft, Yiping Fan, Thomas Confer, Melissa Johnson, Walter J.

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