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@ARTICLE{Kutscher:157608,
author = {L. Kutscher$^*$ and K. Okonechnikov$^*$ and N. Batora and
J. Clark$^*$ and P. B. G. Silva$^*$ and M. Vouri$^*$ and S.
van Rijn$^*$ and L. Sieber$^*$ and B. Statz$^*$ and M. D.
Gearhart and R. Shiraishi and N. Mack$^*$ and B. A. Orr and
A. Korshunov$^*$ and B. L. Gudenas and K. S. Smith and A. L.
Mercier and O. Ayrault and M. Hoshino and M. Kool$^*$ and K.
von Hoff and N. Graf and G. Fleishhack and V. J.
Bardwell$^*$ and S. M. Pfister$^*$ and P. A. Northcott and
D. Kawauchi$^*$},
title = {{F}unctional loss of a noncanonical {BCOR}-{PRC}1.1 complex
accelerates {SHH}-driven medulloblastoma formation.},
journal = {Genes $\&$ development},
volume = {34},
number = {17-18},
issn = {1549-5477},
address = {Cold Spring Harbor, NY},
publisher = {Laboratory Press},
reportid = {DKFZ-2020-01705},
pages = {1161-1176},
year = {2020},
note = {2020 Sep 1;34(17-18):1161-1176#EA:B062#LA:B062#},
abstract = {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.},
cin = {B062 / HD01 / B300},
ddc = {570},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
I:(DE-He78)B300-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32820036},
doi = {10.1101/gad.337584.120},
url = {https://inrepo02.dkfz.de/record/157608},
}