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000292108 1001_ $$00009-0001-6070-0434$$aTsiami, Foteini$$b0
000292108 245__ $$aGenome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.
000292108 260__ $$aLondon$$bBiomed Central$$c2024
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000292108 520__ $$aSonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.
000292108 536__ $$0G:(DE-HGF)POF4-312$$a312 - Funktionelle und strukturelle Genomforschung (POF4-312)$$cPOF4-312$$fPOF IV$$x0
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000292108 650_7 $$2Other$$aCombinatorial treatment
000292108 650_7 $$2Other$$aDNMT1
000292108 650_7 $$2Other$$aFunctional genomics
000292108 650_7 $$2Other$$aMedulloblastoma
000292108 650_7 $$2Other$$aSHH pathway
000292108 650_7 $$2Other$$aSynergy
000292108 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDNA (Cytosine-5-)-Methyltransferase 1
000292108 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000292108 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDNMT1 protein, human
000292108 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDnmt1 protein, mouse
000292108 650_7 $$2NLM Chemicals$$aSmoothened Receptor
000292108 650_2 $$2MeSH$$aMedulloblastoma: genetics
000292108 650_2 $$2MeSH$$aMedulloblastoma: metabolism
000292108 650_2 $$2MeSH$$aMedulloblastoma: pathology
000292108 650_2 $$2MeSH$$aAnimals
000292108 650_2 $$2MeSH$$aDNA (Cytosine-5-)-Methyltransferase 1: genetics
000292108 650_2 $$2MeSH$$aDNA (Cytosine-5-)-Methyltransferase 1: metabolism
000292108 650_2 $$2MeSH$$aHedgehog Proteins: metabolism
000292108 650_2 $$2MeSH$$aHedgehog Proteins: genetics
000292108 650_2 $$2MeSH$$aCRISPR-Cas Systems
000292108 650_2 $$2MeSH$$aCerebellar Neoplasms: genetics
000292108 650_2 $$2MeSH$$aCerebellar Neoplasms: metabolism
000292108 650_2 $$2MeSH$$aCerebellar Neoplasms: pathology
000292108 650_2 $$2MeSH$$aHumans
000292108 650_2 $$2MeSH$$aMice
000292108 650_2 $$2MeSH$$aCell Line, Tumor
000292108 650_2 $$2MeSH$$aSmoothened Receptor: genetics
000292108 650_2 $$2MeSH$$aSmoothened Receptor: metabolism
000292108 650_2 $$2MeSH$$aGene Knockout Techniques: methods
000292108 7001_ $$00000-0002-1317-7847$$aLago, Chiara$$b1
000292108 7001_ $$aPozza, Noemi$$b2
000292108 7001_ $$00000-0003-1210-3210$$aPiccioni, Federica$$b3
000292108 7001_ $$00000-0003-3007-7124$$aZhao, Xuesong$$b4
000292108 7001_ $$aLülsberg, Fabienne$$b5
000292108 7001_ $$00000-0001-5122-861X$$aRoot, David E$$b6
000292108 7001_ $$00000-0002-5983-3782$$aTiberi, Luca$$b7
000292108 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b8$$udkfz
000292108 7001_ $$00000-0002-9168-6209$$aSchittenhelm, Jens$$b9
000292108 7001_ $$00000-0002-4175-4760$$aBandopadhayay, Pratiti$$b10
000292108 7001_ $$00000-0001-9850-8432$$aSegal, Rosalind A$$b11
000292108 7001_ $$0P:(DE-He78)d53ff17be4b468909d803eccd92df3d6$$aTabatabai, Ghazaleh$$b12$$udkfz
000292108 7001_ $$00000-0003-2935-6919$$aMerk, Daniel J$$b13
000292108 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-024-01831-x$$gVol. 12, no. 1, p. 125$$n1$$p125$$tActa Neuropathologica Communications$$v12$$x2051-5960$$y2024
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