Home > Publications database > Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma. > print

001     292108
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100 1 _ |a Tsiami, Foteini
|0 0009-0001-6070-0434
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245 _ _ |a Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.
260 _ _ |a London
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|b Biomed Central
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520 _ _ |a Sonic 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.
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650 _ 7 |a Combinatorial treatment
|2 Other
650 _ 7 |a DNMT1
|2 Other
650 _ 7 |a Functional genomics
|2 Other
650 _ 7 |a Medulloblastoma
|2 Other
650 _ 7 |a SHH pathway
|2 Other
650 _ 7 |a Synergy
|2 Other
650 _ 7 |a DNA (Cytosine-5-)-Methyltransferase 1
|0 EC 2.1.1.37
|2 NLM Chemicals
650 _ 7 |a Hedgehog Proteins
|2 NLM Chemicals
650 _ 7 |a DNMT1 protein, human
|0 EC 2.1.1.37
|2 NLM Chemicals
650 _ 7 |a Dnmt1 protein, mouse
|0 EC 2.1.1.37
|2 NLM Chemicals
650 _ 7 |a Smoothened Receptor
|2 NLM Chemicals
650 _ 2 |a Medulloblastoma: genetics
|2 MeSH
650 _ 2 |a Medulloblastoma: metabolism
|2 MeSH
650 _ 2 |a Medulloblastoma: pathology
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a DNA (Cytosine-5-)-Methyltransferase 1: genetics
|2 MeSH
650 _ 2 |a DNA (Cytosine-5-)-Methyltransferase 1: metabolism
|2 MeSH
650 _ 2 |a Hedgehog Proteins: metabolism
|2 MeSH
650 _ 2 |a Hedgehog Proteins: genetics
|2 MeSH
650 _ 2 |a CRISPR-Cas Systems
|2 MeSH
650 _ 2 |a Cerebellar Neoplasms: genetics
|2 MeSH
650 _ 2 |a Cerebellar Neoplasms: metabolism
|2 MeSH
650 _ 2 |a Cerebellar Neoplasms: pathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Smoothened Receptor: genetics
|2 MeSH
650 _ 2 |a Smoothened Receptor: metabolism
|2 MeSH
650 _ 2 |a Gene Knockout Techniques: methods
|2 MeSH
700 1 _ |a Lago, Chiara
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700 1 _ |a Pozza, Noemi
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700 1 _ |a Piccioni, Federica
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700 1 _ |a Zhao, Xuesong
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700 1 _ |a Lülsberg, Fabienne
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700 1 _ |a Root, David E
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700 1 _ |a Tiberi, Luca
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700 1 _ |a Kool, Marcel
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700 1 _ |a Schittenhelm, Jens
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700 1 _ |a Bandopadhayay, Pratiti
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700 1 _ |a Segal, Rosalind A
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700 1 _ |a Tabatabai, Ghazaleh
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700 1 _ |a Merk, Daniel J
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773 _ _ |a 10.1186/s40478-024-01831-x
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