TY  - JOUR
AU  - Kutscher, Lena
AU  - Okonechnikov, Konstantin
AU  - Batora, Nadja
AU  - Clark, Jessica
AU  - Silva, Patricia B G
AU  - Vouri, Mikaella
AU  - van Rijn, Sjoerd
AU  - Sieber, Laura
AU  - Statz, Britta
AU  - Gearhart, Micah D
AU  - Shiraishi, Ryo
AU  - Mack, Norman
AU  - Orr, Brent A
AU  - Korshunov, Andrey
AU  - Gudenas, Brian L
AU  - Smith, Kyle S
AU  - Mercier, Audrey L
AU  - Ayrault, Olivier
AU  - Hoshino, Mikio
AU  - Kool, Marcel
AU  - von Hoff, Katja
AU  - Graf, Norbert
AU  - Fleishhack, Gudrun
AU  - Bardwell, Vivian J
AU  - Pfister, Stefan M
AU  - Northcott, Paul A
AU  - Kawauchi, Daisuke
TI  - Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.
JO  - Genes & development
VL  - 34
IS  - 17-18
SN  - 1549-5477
CY  - Cold Spring Harbor, NY
PB  - Laboratory Press
M1  - DKFZ-2020-01705
SP  - 1161-1176
PY  - 2020
N1  - 2020 Sep 1;34(17-18):1161-1176#EA:B062#LA:B062#
AB  - Medulloblastoma is a malignant 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 corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10 ) in GNPs during development. This mutation 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 fully penetrant medulloblastomas. In Ptch1+/-;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32820036
DO  - DOI:10.1101/gad.337584.120
UR  - https://inrepo02.dkfz.de/record/157608
ER  -