TY - JOUR
T1 - K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas
AU - Jessa, Selin
AU - Mohammadnia, Abdulshakour
AU - Harutyunyan, Ashot S.
AU - Hulswit, Maud
AU - Varadharajan, Srinidhi
AU - Lakkis, Hussein
AU - Kabir, Nisha
AU - Bashardanesh, Zahedeh
AU - Hébert, Steven
AU - Faury, Damien
AU - Vladoiu, Maria C.
AU - Worme, Samantha
AU - Coutelier, Marie
AU - Krug, Brian
AU - Faria Andrade, Augusto
AU - Pathania, Manav
AU - Bajic, Andrea
AU - Weil, Alexander G.
AU - Ellezam, Benjamin
AU - Atkinson, Jeffrey
AU - Dudley, Roy W.R.
AU - Farmer, Jean Pierre
AU - Perreault, Sebastien
AU - Garcia, Benjamin A.
AU - Larouche, Valérie
AU - Blanchette, Mathieu
AU - Garzia, Livia
AU - Bhaduri, Aparna
AU - Ligon, Keith L.
AU - Bandopadhayay, Pratiti
AU - Taylor, Michael D.
AU - Mack, Stephen C.
AU - Jabado, Nada
AU - Kleinman, Claudia L.
N1 - Funding Information:
We thank the patients and their families for their invaluable contributions to this research, without whom it would be impossible. This work was supported by funding from A Large-Scale Applied Research Project grant from Genome Quebec, Genome Canada, the Government of Canada, and the Ministère de l'Économie, de la Science et de l’Innovation du Québec, with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario to N.J., M.D.T., C.L.K. Fondation Charles Bruneau to N.J., US National Institutes of Health (NIH) (grant P01-CA196539 to N.J. and grants R01CA148699 and R01CA159859 to M.D.T.); the Canadian Institutes for Health Research (CIHR) (grants MOP-286756 and FDN-154307 to N.J. and grant PJT-156086 to C.L.K.); the Canadian Cancer Society (CCSRI) (grant 705182) and the Fonds de Recherche du Québec en Santé (FRQS) salary award to C.L.K.; NSERC (RGPIN-2016-04911) to C.L.K.; CFI Leaders Opportunity Fund 33902 to C.L.K., Genome Canada Science Technology Innovation Centre, Compute Canada Resource Allocation Project (WST-164-AB). Data analyses were enabled by compute and storage resources provided by Compute Canada and Calcul Québec. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the FRQS. This work was performed within the context of the International CHildhood Astrocytoma INtegrated Genomic and Epigenomic (ICHANGE) consortium with funding from Genome Canada and Genome Quebec. S.J. is supported by a fellowship from CIHR. We also acknowledge support from the We Love You Connie, Poppies for Irini and Kat D Strong Foundations (N.J.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We acknowledge the contributions of D. Marchione and J. Wojcik in MS work.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/12
Y1 - 2022/12
N2 - Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate.
AB - Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate.
UR - http://www.scopus.com/inward/record.url?scp=85143289035&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01205-w
DO - 10.1038/s41588-022-01205-w
M3 - Article
C2 - 36471070
AN - SCOPUS:85143289035
SN - 1061-4036
VL - 54
SP - 1865
EP - 1880
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -