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KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE211030 | GEO | 2023/10/25

REPOSITORIES: GEO

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KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [ATAC-seq]

Project description:The major cause for treatment failure, morbidity and mortality amongst medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in SHH-driven medulloblastoma (SHH-MB) patients remain largely unknown. In this study we used mouse models of SHH-MB to define a tumor suppressive role of KMT2D (MLL4), a gene frequently mutated in the most metastatic β-subtype. Strikingly, heterozygous loss of Kmt2d in conjunction with aberrant activation of the SHH pathway causes highly penetrant disease with decreased survival, hindbrain invasion and spinal cord metastasis. Loss of Kmt2d shifts the transcriptional and chromatin landscape of primary and metastatic tumor cells to preferentially upregulate pathways and genes associated with advanced stage cancer and metastasis including TGFβ, Notch, Atoh1, Sox2/9 and Myc. Our study provides strong evidence that secondary mutations in KMT2D will have prognostic value for identifying SHH-MB patients that are likely to develop metastasis.

2023-10-25 | GSE211029 | GEO