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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma.

ABSTRACT: Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma.

PROVIDER: PRJNA1083708 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR28171101_1.fastq.gz	Fastqsanger.gz
	SRR28171101_2.fastq.gz	Fastqsanger.gz
	SRR28171102_1.fastq.gz	Fastqsanger.gz
	SRR28171102_2.fastq.gz	Fastqsanger.gz

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma

Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous germline Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated MBs in SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved HDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [bulkRNA]

Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated tumors in SHH-3. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [DNA_methylation_array]

Project description:Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [DNA_methylation_array]

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [bulkRNA]

Project description:Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [bulkRNA]

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Genetic modeling of ELP1-associated Sonic Hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target

Project description:Germline loss-of-function (LOF) variants in Elongator Acetyltransferase Complex Subunit 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of premalignancy in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing a plausible explanation for the exclusivity of ELP1-associated MBs in the SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics targeting MDM2 as a rational treatment option.

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma.

Project description:This SuperSeries is composed of the SubSeries listed below.

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Chronic Crebbp knockout in cerebellar granule neuron precursors [development]

Project description:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine granule neuron precursors, chronically induced at embryonic stages of development.

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [DNA_methylation_array]

Project description:Mouse tumor methylation profiling by MouseMethylation Beadchips (MM285) platform

2025-04-09 | GSE260660 | GEO

Gene expression of cerebellar granule cell layer

Project description:We performed gene-expression analysis of mouse cerebellar granule cell layer as compared to that of Purkinje cells. DNA microarray analysis detected genes in cerebellar granule cell layer, most of which are classified into functional molecule categories. Our comparative analysis between Purkinje cells and the granule cell layer showed that the characteristic expression pattern in Purkinje cells was particularly represented by M-bM-^@M-^\the neural communication systemM-bM-^@M-^] components. Pukinje cells and granule cell layer of the mouse cerebellum were collected by laser microdissection for RNA extraction and hybridization on Affymetrix microarrays.

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