TY - JOUR
T1 - ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
AU - Hoeman, Christine Marie
AU - Cordero, Francisco J.
AU - Hu, Guo
AU - Misuraca, Katie
AU - Romero, Megan M.
AU - Cardona, Herminio J.
AU - Nazarian, Javad
AU - Hashizume, Rintaro
AU - McLendon, Roger
AU - Yu, Paul
AU - Procissi, Daniele
AU - Gadd, Samantha L
AU - Becher, Oren Josh
N1 - Funding Information:
The authors would like to thank A. Chung and K. Barton for their technical support. RCAS-Noggin was generously provided by Cliff Tabin. RCAS-BMP4 was generously provided by Arhat Abzhanov. RCAS-Stat3 was generously provided by Ganesh Rao. This work was supported by the Damon Runyon Cancer Research Foundation, the Stewart Trust Foundation, R01 CA197313, K02-NS086917, Madox’s Warriors, Fly the Kite Foundation, Cristian Rivera Foundation, and John McNicholas Pediatric Brain Tumor Foundation.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/3/4
Y1 - 2019/3/4
N2 - Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.
AB - Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.
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U2 - 10.1038/s41467-019-08823-9
DO - 10.1038/s41467-019-08823-9
M3 - Article
C2 - 30833574
AN - SCOPUS:85062420207
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1023
ER -