KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis
Reeti Mayur Sanghrajka,
Richard Koche,
Hector Medrano,
Salsabiel El Nagar,
Daniel N. Stephen,
Zhimin Lao,
N. Sumru Bayin,
Kai Ge,
Alexandra L. Joyner
Affiliations
Reeti Mayur Sanghrajka
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA; Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
Richard Koche
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Hector Medrano
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
Salsabiel El Nagar
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
Daniel N. Stephen
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
Zhimin Lao
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
N. Sumru Bayin
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
Kai Ge
Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
Alexandra L. Joyner
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA; Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA; Corresponding author
Summary: 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.
