KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis

被引:10
作者
Sanghrajka, Reeti Mayur [1 ,2 ]
Koche, Richard [3 ]
Medrano, Hector [1 ]
El Nagar, Salsabiel [1 ]
Stephen, Daniel N. [1 ]
Lao, Zhimin [1 ]
Bayin, N. Sumru [1 ,5 ,6 ]
Ge, Kai [4 ]
Joyner, Alexandra L. [1 ,2 ]
机构
[1] Sloan Kettering Inst, Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA
[2] Weill Cornell Grad Sch Med Sci, Biochem Cell & Mol Biol Program, New York, NY 10065 USA
[3] Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, New York, NY 10065 USA
[4] Natl Inst Diabet & Digest & Kidney Dis, Natl Inst Hlth NIH, Adipocyte Biol & Gene Regulat Sect, Bethesda, MD USA
[5] Univ Cambridge, Canc Res UK Gurdon Inst, Wellcome Trust, Cambridge, England
[6] Univ Cambridge, Dept Physiol, Dev & Neurosci, Cambridge, Cambridgeshire, England
关键词
MOLECULAR SUBGROUPS; CHILDHOOD MEDULLOBLASTOMA; MOUSE MODEL; CANCER; MICE; HETEROGENEITY; LOCALIZATION; DISRUPTION; COMPLEXITY; LANDSCAPE;
D O I
10.1016/j.isci.2023.107831
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-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 (TGF beta, Notch, Atoh1, Sox2, and Myc). Thus, secondary heterozygous KMT2D mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis.
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页数:27
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