Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Centre for Discovery in Cancer Research McMaster University Hamilton ON Canada

Computational Biology Program Ontario Institute for Cancer Research Toronto Canada

Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada

Department of Cellular and Molecular Medicine University of California at San Diego La Jolla CA USA

Department of Chemistry CZ Openscreen Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of Medical Biophysics University of Toronto Toronto Canada

Department of Molecular Genetics University of Toronto Toronto Canada

Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty University Hospital Düsseldorf Düsseldorf Germany

Departments of Pharmacology and Medicine University of California San Diego School of Medicine Sanford Consortium for Regenerative Medicine La Jolla CA USA

Donnelly Centre Department of Molecular Genetics University of Toronto Toronto Canada

Herbert Irving Comprehensive Cancer Center Department of Physiology and Cellular Biophysics Columbia University Medical Center New York NY USA

International Clinical Research Center St Anne's University Hospital in Brno 602 00 Brno Czech Republic

McMaster University Department of Pediatrics Hamilton Canada

McMaster University Departments of Neuropathology Hamilton Canada

McMaster University Departments of Pediatrics Hematology and Oncology Division Hamilton Canada

Michael G DeGroote School of Medicine McMaster University Hamilton Canada

Sanford Consortium for Regenerative Medicine La Jolla CA USA

Stem Cell Program University of California San Diego La Jolla CA USA

Surgery Faculty of Health Sciences McMaster University Hamilton ON Canada

Tumor Initiation and Maintenance Program National Cancer Institute Designated Cancer Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA

University Health Network Toronto ON Canada

Vector Institute Toronto Toronto ON Canada

Erratum In

Nat Commun. 2023 Jan 10;14(1):136. doi: 10.1038/s41467-023-35816-6. PubMed

See more in PubMed

Taylor MD, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–472. doi: 10.1007/s00401-011-0922-z. PubMed DOI PMC

Kool M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012;123:473–484. doi: 10.1007/s00401-012-0958-8. PubMed DOI PMC

Forget A, et al. Aberrant ERBB4-SRC signaling as a hallmark of group 4 medulloblastoma revealed by integrative phosphoproteomic profiling. Cancer Cell. 2018;34:379–395.e377. doi: 10.1016/j.ccell.2018.08.002. PubMed DOI

Ramaswamy, V. et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol. 10.1007/s00401-016-1569-6 (2016). PubMed PMC

Cho YJ, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 2011;29:1424–1430. doi: 10.1200/JCO.2010.28.5148. PubMed DOI PMC

Cavalli FMG, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell. 2017;31:737–754. doi: 10.1016/j.ccell.2017.05.005. PubMed DOI PMC

Bandopadhayay P, et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin. Cancer Res. 2014;20:912–925. doi: 10.1158/1078-0432.CCR-13-2281. PubMed DOI PMC

Hill RM, et al. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer Cell. 2015;27:72–84. doi: 10.1016/j.ccell.2014.11.002. PubMed DOI PMC

Ecker J, et al. Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol. Commun. 2015;3:22. doi: 10.1186/s40478-015-0201-7. PubMed DOI PMC

Gottardo NG, et al. Medulloblastoma down under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol. 2014;127:189–201. doi: 10.1007/s00401-013-1213-7. PubMed DOI PMC

Archer TC, et al. Proteomics, post-translational modifications, and integrative analyses reveal molecular heterogeneity within medulloblastoma subgroups. Cancer Cell. 2018;34:396–410. doi: 10.1016/j.ccell.2018.08.004. PubMed DOI PMC

Zomerman WW, et al. Identification of two protein-signaling states delineating transcriptionally heterogeneous human medulloblastoma. Cell Rep. 2018;22:3206–3216. doi: 10.1016/j.celrep.2018.02.089. PubMed DOI

Grabowski P. Alternative splicing takes shape during neuronal development. Curr. Opin. Genet. Dev. 2011;21:388–394. doi: 10.1016/j.gde.2011.03.005. PubMed DOI

Miura P, Shenker S, Andreu-Agullo C, Westholm JO, Lai EC. Widespread and extensive lengthening of 3’ UTRs in the mammalian brain. Genome Res. 2013;23:812–825. doi: 10.1101/gr.146886.112. PubMed DOI PMC

Wang ET, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456:470–476. doi: 10.1038/nature07509. PubMed DOI PMC

Xu Q, Modrek B, Lee C. Genome-wide detection of tissue-specific alternative splicing in the human transcriptome. Nucleic Acids Res. 2002;30:3754–3766. doi: 10.1093/nar/gkf492. PubMed DOI PMC

Yeo GW, Van Nostrand E, Holste D, Poggio T, Burge CB. Identification and analysis of alternative splicing events conserved in human and mouse. Proc. Natl Acad. Sci. USA. 2005;102:2850–2855. doi: 10.1073/pnas.0409742102. PubMed DOI PMC

Sakakibara S, et al. Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev. Biol. 1996;176:230–242. doi: 10.1006/dbio.1996.0130. PubMed DOI

Sakakibara S, Okano H. Expression of neural RNA-binding proteins in the postnatal CNS: implications of their roles in neuronal and glial cell development. J. Neurosci. 1997;17:8300–8312. doi: 10.1523/JNEUROSCI.17-21-08300.1997. PubMed DOI PMC

Chen J, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522–526. doi: 10.1038/nature11287. PubMed DOI PMC

Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis. Nature. 2012;488:527–530. doi: 10.1038/nature11344. PubMed DOI PMC

Schepers AG, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337:730–735. doi: 10.1126/science.1224676. PubMed DOI

Hemmati HD, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl Acad. Sci. USA. 2003;100:15178–15183. doi: 10.1073/pnas.2036535100. PubMed DOI PMC

Singh, S., Clarke, I., Terasaki, M. & Bonn, V. Identification of a cancer stem cell in human brain tumors. Cancer Res.63, 5821–5828 (2003). PubMed

Singh SK, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401. doi: 10.1038/nature03128. PubMed DOI

Kanemura Y, et al. Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity. Differentiation. 2001;68:141–152. doi: 10.1046/j.1432-0436.2001.680208.x. PubMed DOI

Toda M, et al. Expression of the neural RNA-binding protein Musashi1 in human gliomas. Glia. 2001;34:1–7. doi: 10.1002/glia.1034. PubMed DOI

Sanchez-Diaz PC, Burton TL, Burns SC, Hung JY, Penalva LO. Musashi1 modulates cell proliferation genes in the medulloblastoma cell line Daoy. BMC Cancer. 2008;8:280. doi: 10.1186/1471-2407-8-280. PubMed DOI PMC

Chen HY, et al. Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma. Oncotarget. 2016;7:42485–42501. doi: 10.18632/oncotarget.9890. PubMed DOI PMC

Cox JL, et al. The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells. PLoS ONE. 2013;8:e62857. doi: 10.1371/journal.pone.0062857. PubMed DOI PMC

Dahlrot RH, et al. Prognostic value of Musashi-1 in gliomas. J. Neurooncol. 2013;115:453–461. doi: 10.1007/s11060-013-1246-8. PubMed DOI

Dahlrot RH. The prognostic value of clinical factors and cancer stem cell-related markers in gliomas. Dan. Med. J. 2014;61:B4944. PubMed

de Araujo PR, et al. Musashi1 impacts radio-resistance in glioblastoma by controlling DNA-protein kinase catalytic subunit. Am. J. Pathol. 2016;186:2271–2278. doi: 10.1016/j.ajpath.2016.05.020. PubMed DOI PMC

Johannessen TC, et al. Highly infiltrative brain tumours show reduced chemosensitivity associated with a stem cell-like phenotype. Neuropathol. Appl. Neurobiol. 2009;35:380–393. doi: 10.1111/j.1365-2990.2009.01008.x. PubMed DOI

Lagadec C, et al. The RNA-binding protein Musashi-1 regulates proteasome subunit expression in breast cancer- and glioma-initiating cells. Stem Cells. 2014;32:135–144. doi: 10.1002/stem.1537. PubMed DOI PMC

Muto J, et al. RNA-binding protein Musashi1 modulates glioma cell growth through the post-transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways. PLoS ONE. 2012;7:e33431. doi: 10.1371/journal.pone.0033431. PubMed DOI PMC

Vo DT, et al. The RNA-binding protein Musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis. Am. J. Pathol. 2012;181:1762–1772. doi: 10.1016/j.ajpath.2012.07.031. PubMed DOI PMC

Vo DT, et al. The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs. RNA Biol. 2011;8:817–828. doi: 10.4161/rna.8.5.16041. PubMed DOI

Vo DT, et al. The oncogenic RNA-binding protein Musashi1 is regulated by HuR via mRNA translation and stability in glioblastoma cells. Mol. Cancer Res. 2012;10:143–155. doi: 10.1158/1541-7786.MCR-11-0208. PubMed DOI PMC

Uren PJ, et al. RNA-binding protein musashi1 is a central regulator of adhesion pathways in glioblastoma. Mol. Cell Biol. 2015;35:2965–2978. doi: 10.1128/MCB.00410-15. PubMed DOI PMC

Potten CS, et al. Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation. 2003;71:28–41. doi: 10.1046/j.1432-0436.2003.700603.x. PubMed DOI

Li D, et al. Msi-1 is a predictor of survival and a novel therapeutic target in colon cancer. Ann. Surg. Oncol. 2011;18:2074–2083. doi: 10.1245/s10434-011-1567-9. PubMed DOI

Ito T, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466:765–768. doi: 10.1038/nature09171. PubMed DOI PMC

Van Nostrand, E. L. et al. Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat. Methods13, 508–514 (2016). PubMed PMC

Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–760. doi: 10.1038/nature05236. PubMed DOI

Lin, J. C. et al. MSI1 associates glioblastoma radioresistance via homologous recombination repair, tumor invasion and cancer stem-like cell properties. Radiother. Oncol. 10.1016/j.radonc.2018.09.014 (2018). PubMed

Chen HY, et al. Musashi-1 promotes chemoresistant granule formation by PKR/eIF2alpha signalling cascade in refractory glioblastoma. Biochim. Biophys. Acta. 2018;1864:1850–1861. doi: 10.1016/j.bbadis.2018.02.017. PubMed DOI

Panosyan EH, et al. Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation. Pediatr. Blood Cancer. 2010;55:644–651. doi: 10.1002/pbc.22627. PubMed DOI PMC

Kanai R, et al. Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of gamma34.5-mediated virulence. Gene Ther. 2006;13:106–116. doi: 10.1038/sj.gt.3302636. PubMed DOI

Kagara N, et al. Epigenetic regulation of cancer stem cell genes in triple-negative breast cancer. Am. J. Pathol. 2012;181:257–267. doi: 10.1016/j.ajpath.2012.03.019. PubMed DOI

Yi C, et al. Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells. RNA Biol. 2018;15:1420–1432. doi: 10.1080/15476286.2018.1539607. PubMed DOI PMC

Lan L, et al. Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins. BMC Cancer. 2018;18:809. doi: 10.1186/s12885-018-4704-z. PubMed DOI PMC

Velasco MX, et al. Antagonism between the RNA-binding protein Musashi1 and miR-137 and its potential impact on neurogenesis and glioblastoma development. RNA. 2019;25:768–782. doi: 10.1261/rna.069211.118. PubMed DOI PMC

Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999;397:164–168. doi: 10.1038/16476. PubMed DOI

Jacobs JJ, et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999;13:2678–2690. doi: 10.1101/gad.13.20.2678. PubMed DOI PMC

Leung C, et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature. 2004;428:337–341. doi: 10.1038/nature02385. PubMed DOI

Toledo CM, et al. Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in glioblastoma stem-like cells. Cell Rep. 2015;13:2425–2439. doi: 10.1016/j.celrep.2015.11.021. PubMed DOI PMC

Sakakibara S, et al. RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Proc. Natl Acad. Sci. USA. 2002;99:15194–15199. doi: 10.1073/pnas.232087499. PubMed DOI PMC

Pei Y, et al. An animal model of MYC-driven medulloblastoma. Cancer Cell. 2012;21:155–167. doi: 10.1016/j.ccr.2011.12.021. PubMed DOI PMC

Fox RG, et al. Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature. 2016;534:407–411. doi: 10.1038/nature17988. PubMed DOI PMC

Li Y, Choi PS, Casey SC, Felsher DW. Activation of Cre recombinase alone can induce complete tumor regression. PLoS ONE. 2014;9:e107589. doi: 10.1371/journal.pone.0107589. PubMed DOI PMC

McFarland JM, et al. Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration. Nat. Commun. 2018;9:4610. doi: 10.1038/s41467-018-06916-5. PubMed DOI PMC

Ohyama T, et al. Structure of Musashi1 in a complex with target RNA: the role of aromatic stacking interactions. Nucleic Acids Res. 2012;40:3218–3231. doi: 10.1093/nar/gkr1139. PubMed DOI PMC

Northcott PA, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488:49–56. doi: 10.1038/nature11327. PubMed DOI PMC

Kool M, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE. 2008;3:e3088. doi: 10.1371/journal.pone.0003088. PubMed DOI PMC

Ferrucci V, et al. Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-beta-OTX2-SNAIL via PTEN inhibition. Brain. 2018;141:1300–1319. doi: 10.1093/brain/awy039. PubMed DOI

McCarthy DJ, Smyth GK. Testing significance relative to a fold-change threshold is a TREAT. Bioinformatics. 2009;25:765–771. doi: 10.1093/bioinformatics/btp053. PubMed DOI PMC

Northcott PA, et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 2011;29:1408–1414. doi: 10.1200/JCO.2009.27.4324. PubMed DOI PMC

Northcott PA, et al. The whole-genome landscape of medulloblastoma subtypes. Nature. 2017;547:311–317. doi: 10.1038/nature22973. PubMed DOI PMC

Baltz AG, et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell. 2012;46:674–690. doi: 10.1016/j.molcel.2012.05.021. PubMed DOI

Castello A, et al. System-wide identification of RNA-binding proteins by interactome capture. Nat. Protoc. 2013;8:491–500. doi: 10.1038/nprot.2013.020. PubMed DOI

Keene JD, Tenenbaum SA. Eukaryotic mRNPs may represent posttranscriptional operons. Mol. Cell. 2002;9:1161–1167. doi: 10.1016/S1097-2765(02)00559-2. PubMed DOI

Doma MK, Parker R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature. 2006;440:561–564. doi: 10.1038/nature04530. PubMed DOI PMC

Frischmeyer PA, et al. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science. 2002;295:2258–2261. doi: 10.1126/science.1067338. PubMed DOI

Schmidt EK, Clavarino G, Ceppi M, Pierre P. SUnSET, a nonradioactive method to monitor protein synthesis. Nat. Methods. 2009;6:275–277. doi: 10.1038/nmeth.1314. PubMed DOI

Lavallee-Adam M, Rauniyar N, McClatchy DB, Yates JR., 3rd PSEA-Quant: a protein set enrichment analysis on label-free and label-based protein quantification data. J. Proteome Res. 2014;13:5496–5509. doi: 10.1021/pr500473n. PubMed DOI PMC

Kolde R, Laur S, Adler P, Vilo J. Robust rank aggregation for gene list integration and meta-analysis. Bioinformatics. 2012;28:573–580. doi: 10.1093/bioinformatics/btr709. PubMed DOI PMC

Futreal PA, et al. A census of human cancer genes. Nat. Rev. Cancer. 2004;4:177–183. doi: 10.1038/nrc1299. PubMed DOI PMC

Jones DT, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488:100–105. doi: 10.1038/nature11284. PubMed DOI PMC

Pugh TJ, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488:106–110. doi: 10.1038/nature11329. PubMed DOI PMC

Parsons DW, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331:435–439. doi: 10.1126/science.1198056. PubMed DOI PMC

Northcott PA, et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123:615–626. doi: 10.1007/s00401-011-0899-7. PubMed DOI PMC

Pomeroy SL, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002;415:436–442. doi: 10.1038/415436a. PubMed DOI

Robinson G, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488:43–48. doi: 10.1038/nature11213. PubMed DOI PMC

Bowman RL, Wang Q, Carro A, Verhaak RG, Squatrito M. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19:139–141. doi: 10.1093/neuonc/now247. PubMed DOI PMC

Wu G, Haw R. Functional interaction network construction and analysis for disease discovery. Methods Mol. Biol. 2017;1558:235–253. doi: 10.1007/978-1-4939-6783-4_11. PubMed DOI

Reimand J, et al. Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap. Nat. Protoc. 2019;14:482–517. doi: 10.1038/s41596-018-0103-9. PubMed DOI PMC

Paczkowska, M. et al. Integrative pathway enrichment analysis of multivariate omics data. Nat. Commun.11, 735 (2020). PubMed PMC

Petralia F, et al. Integrated proteogenomic characterization across major histological types of pediatric brain cancer. Cell. 2020;183:1962–1985.e1931. doi: 10.1016/j.cell.2020.10.044. PubMed DOI PMC

Schwanhausser B, et al. Global quantification of mammalian gene expression control. Nature. 2011;473:337–342. doi: 10.1038/nature10098. PubMed DOI

Vogel C, et al. Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line. Mol. Syst. Biol. 2010;6:400. doi: 10.1038/msb.2010.59. PubMed DOI PMC

Castello A, et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell. 2012;149:1393–1406. doi: 10.1016/j.cell.2012.04.031. PubMed DOI

Katz Y, et al. Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state. Elife. 2014;3:e03915. doi: 10.7554/eLife.03915. PubMed DOI PMC

Fan X, et al. Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res. 2004;64:7787–7793. doi: 10.1158/0008-5472.CAN-04-1446. PubMed DOI

Garzia L, et al. MicroRNA-199b-5p impairs cancer stem cells through negative regulation of HES1 in medulloblastoma. PLoS ONE. 2009;4:e4998. doi: 10.1371/journal.pone.0004998. PubMed DOI PMC

Zhong W, Feder JN, Jiang MM, Jan LY, Jan YN. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron. 1996;17:43–53. doi: 10.1016/S0896-6273(00)80279-2. PubMed DOI

Qin H, et al. A novel transmembrane protein recruits numb to the plasma membrane during asymmetric cell division. J. Biol. Chem. 2004;279:11304–11312. doi: 10.1074/jbc.M311733200. PubMed DOI

Petersen PH, Zou K, Hwang JK, Jan YN, Zhong W. Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature. 2002;419:929–934. doi: 10.1038/nature01124. PubMed DOI

Petersen PH, Zou K, Krauss S, Zhong W. Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Nat. Neurosci. 2004;7:803–811. doi: 10.1038/nn1289. PubMed DOI

Rasin MR, et al. Numb and Numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors. Nat. Neurosci. 2007;10:819–827. doi: 10.1038/nn1924. PubMed DOI

Imai T, et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol. Cell Biol. 2001;21:3888–3900. doi: 10.1128/MCB.21.12.3888-3900.2001. PubMed DOI PMC

Zearfoss NR, et al. A conserved three-nucleotide core motif defines Musashi RNA binding specificity. J. Biol. Chem. 2014;289:35530–35541. doi: 10.1074/jbc.M114.597112. PubMed DOI PMC

Rentas S, et al. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells. Nature. 2016;532:508–511. doi: 10.1038/nature17665. PubMed DOI PMC

Hashimoto K, Tsuji Y. Arsenic-induced activation of the homeodomain-interacting protein kinase 2 (HIPK2) to cAMP-response element binding protein (CREB) axis. J. Mol. Biol. 2017;429:64–78. doi: 10.1016/j.jmb.2016.11.015. PubMed DOI PMC

Blough RI, et al. Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome. Am. J. Med. Genet. 2000;90:29–34. doi: 10.1002/(SICI)1096-8628(20000103)90:1<29::AID-AJMG6>3.0.CO;2-Z. PubMed DOI

Bourdeaut F, et al. Rubinstein-Taybi syndrome predisposing to non-WNT, non-SHH, group 3 medulloblastoma. Pediatr. Blood Cancer. 2014;61:383–386. doi: 10.1002/pbc.24765. PubMed DOI

Zhang J, et al. Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. Nat. Neurosci. 2007;10:77–86. doi: 10.1038/nn1816. PubMed DOI PMC

Chalazonitis A, et al. Homeodomain interacting protein kinase 2 regulates postnatal development of enteric dopaminergic neurons and glia via BMP signaling. J. Neurosci. 2011;31:13746–13757. doi: 10.1523/JNEUROSCI.1078-11.2011. PubMed DOI PMC

Kondo, S. et al. Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1). Proc. Natl Acad. Sci. USA100, 5431–5436 (2003). PubMed PMC

Milde T, et al. HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J. Neurooncol. 2012;110:335–348. doi: 10.1007/s11060-012-0978-1. PubMed DOI

Subapanditha MK, Adile AA, Venugopal C, Singh SK. Flow cytometric analysis of brain tumor stem cells. Methods Mol. Biol. 2019;1869:69–77. doi: 10.1007/978-1-4939-8805-1_6. PubMed DOI

Robertson D, Savage K, Reis-Filho JS, Isacke CM. Multiple immunofluorescence labelling of formalin-fixed paraffin-embedded (FFPE) tissue. BMC Cell Biol. 2008;9:13. doi: 10.1186/1471-2121-9-13. PubMed DOI PMC

Hart T, et al. Evaluation and design of genome-wide CRISPR/SpCas9 knockout screens. G3 (Bethesda) 2017;7:2719–2727. doi: 10.1534/g3.117.041277. PubMed DOI PMC

Mair B, et al. High-throughput genome-wide phenotypic screening via immunomagnetic cell sorting. Nat. Biomed. Eng. 2019;3:796–805. doi: 10.1038/s41551-019-0454-8. PubMed DOI

Brinkman EK, Chen T, Amendola M, van Steensel B. Easy quantitative assessment of genome editing by sequence trace decomposition. Nucleic Acids Res. 2014;42:e168. doi: 10.1093/nar/gku936. PubMed DOI PMC

Lamb J. The Connectivity Map: a new tool for biomedical research. Nat. Rev. Cancer. 2007;7:54–60. doi: 10.1038/nrc2044. PubMed DOI

Smirnov P, et al. PharmacoGx: an R package for analysis of large pharmacogenomic datasets. Bioinformatics. 2016;32:1244–1246. doi: 10.1093/bioinformatics/btv723. PubMed DOI

Corsello SM, et al. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med. 2017;23:405–408. doi: 10.1038/nm.4306. PubMed DOI PMC

Van Nostrand, E. L. et al. A large-scale binding and functional map of human RNA-binding proteins. Nature583, 711–719 (2020). PubMed PMC

Lovci MT, et al. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat. Struct. Mol. Biol. 2013;20:1434–1442. doi: 10.1038/nsmb.2699. PubMed DOI PMC

Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 2008;26:1367–1372. doi: 10.1038/nbt.1511. PubMed DOI

Vizcaino JA, et al. 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 2016;44:11033. doi: 10.1093/nar/gkw880. PubMed DOI PMC

Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA. 2005;102:15545–15550. doi: 10.1073/pnas.0506580102. PubMed DOI PMC

Chen EY, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinforma. 2013;14:128. doi: 10.1186/1471-2105-14-128. PubMed DOI PMC

Kuleshov MV, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–W97. doi: 10.1093/nar/gkw377. PubMed DOI PMC

Reimand J, Kull M, Peterson H, Hansen J, Vilo J. g:Profiler-a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 2007;35:W193–W200. doi: 10.1093/nar/gkm226. PubMed DOI PMC

P’ng C, et al. BPG: Seamless, automated and interactive visualization of scientific data. BMC Bioinforma. 2019;20:42. doi: 10.1186/s12859-019-2610-2. PubMed DOI PMC

Wickham, H. ggplot2: elegant graphics for data analysis. 2nd edn. (Springer International Piublishing, 2016).

Wu G, Feng X, Stein L. A human functional protein interaction network and its application to cancer data analysis. Genome Biol. 2010;11:R53. doi: 10.1186/gb-2010-11-5-r53. PubMed DOI PMC