KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis

The major cause of treatment failure and mortality among medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in Sonic hedgehog-driven medulloblastoma (SHH-MB) patients, however, remain largely unknown. In this study we define a tumor suppressive role of KMT2D (MLL2), a gene frequently mutated in the most metastatic β-subtype. Strikingly, genetic mouse models of SHH-MB demonstrate that heterozygous loss of Kmt2d in conjunction with activation of the SHH pathway causes highly penetrant disease with decreased survival, increased hindbrain invasion and spinal cord metastasis. Loss of Kmt2d attenuates neural differentiation and shifts the transcriptional/chromatin landscape of primary and metastatic tumors toward a decrease in differentiation genes and tumor suppressors and an increase in genes/pathways implicated in advanced stage cancer and metastasis (TGFβ, Notch, Atoh1, Sox2, and Myc). Thus, secondary heterozygous KMT2D mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis. [Display omitted] •Heterozygous and homozygous loss of Kmt2d decreases survival in SHH-MB•Kmt2d mutations increase spinal cord metastasis in two mouse models of SHH-MB•Tumors lacking Kmt2d have decreased expression of neural differentiation genes•Tumors lacking Kmt2d upregulate stem cell maintenance and metastasis genes Genetics; Cancer; Model organism