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Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation

View ORCID ProfileLena M. Kutscher, Konstantin Okonechnikov, Nadja V. Batora, Jessica Clark, Patricia B. G. Silva, Mikaella Vouri, Sjoerd van Rijn, Laura Sieber, Britta Statz, Micah D. Gearhart, Norman Mack, Brent A. Orr, Andrey Korshunov, Audrey L. Mercier, Olivier Ayrault, Marcel Kool, Vivian J. Bardwell, View ORCID ProfileStefan M. Pfister, Paul A. Northcott, View ORCID ProfileDaisuke Kawauchi
doi: https://doi.org/10.1101/2020.02.06.938035
Lena M. Kutscher
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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  • ORCID record for Lena M. Kutscher
Konstantin Okonechnikov
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Nadja V. Batora
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Jessica Clark
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Patricia B. G. Silva
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Mikaella Vouri
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Sjoerd van Rijn
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Laura Sieber
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Britta Statz
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Micah D. Gearhart
3Department of Genetics, Cell Biology and Development, Masonic Cancer Center and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA
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Norman Mack
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Brent A. Orr
4Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA
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Andrey Korshunov
5Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
6Department of Neuropathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
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Audrey L. Mercier
7Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay 91405, France
8Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay 91405, France
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Olivier Ayrault
7Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay 91405, France
8Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay 91405, France
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Marcel Kool
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
9Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands
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Vivian J. Bardwell
3Department of Genetics, Cell Biology and Development, Masonic Cancer Center and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA
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Stefan M. Pfister
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
10Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
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Paul A. Northcott
11Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, USA
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  • For correspondence: d.kawauchi@ncnp.go.jp paul.northcott@stjude.org
Daisuke Kawauchi
1Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
2Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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  • For correspondence: d.kawauchi@ncnp.go.jp paul.northcott@stjude.org
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Abstract

Medulloblastoma is a childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH)-subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs) and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional co-repressor BCOR are recurrent and highly enriched in SHH-medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a germline genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10) in GNPs during development. This leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH-receptor gene Ptch1 resulted in highly penetrant medulloblastomas. In Ptch1+/-;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly upregulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/-;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

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Posted February 10, 2020.
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Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation
Lena M. Kutscher, Konstantin Okonechnikov, Nadja V. Batora, Jessica Clark, Patricia B. G. Silva, Mikaella Vouri, Sjoerd van Rijn, Laura Sieber, Britta Statz, Micah D. Gearhart, Norman Mack, Brent A. Orr, Andrey Korshunov, Audrey L. Mercier, Olivier Ayrault, Marcel Kool, Vivian J. Bardwell, Stefan M. Pfister, Paul A. Northcott, Daisuke Kawauchi
bioRxiv 2020.02.06.938035; doi: https://doi.org/10.1101/2020.02.06.938035
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Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation
Lena M. Kutscher, Konstantin Okonechnikov, Nadja V. Batora, Jessica Clark, Patricia B. G. Silva, Mikaella Vouri, Sjoerd van Rijn, Laura Sieber, Britta Statz, Micah D. Gearhart, Norman Mack, Brent A. Orr, Andrey Korshunov, Audrey L. Mercier, Olivier Ayrault, Marcel Kool, Vivian J. Bardwell, Stefan M. Pfister, Paul A. Northcott, Daisuke Kawauchi
bioRxiv 2020.02.06.938035; doi: https://doi.org/10.1101/2020.02.06.938035

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