Journal
CANCER DISCOVERY
Volume 10, Issue 12, Pages 1968-1987Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0461
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Funding
- A Large-Scale Applied Research Project grant from Genome Quebec
- Genome Canada
- Government of Canada
- Ministere de l'Economie, de la Science et de l'Innovation du Quebec
- Ontario Institute for Cancer Research
- Government of Ontario
- Fondation Charles Bruneau
- NIH [P01-CA196539, R01CA148699, R01CA159859]
- Canadian Institutes for Health Research (CIHR) [MOP-286756, FDN-154307, PJT-156086]
- Canadian Cancer Society (CCSRI) [705182]
- Fonds de Recherche du Quebec en Sante (FRQS) salary award
- NSERC [RGPIN-2016-04911]
- CFI Leaders Opportunity Fund [33902, WST-164-AB]
- Chaire de Recherche Award from the FRQS
- Stand Up To Cancer (SU2C) Canada Cancer Stem Cell Dream Team Research Funding [SU2C-AACR-DT-19-15]
- Government of Canada through Genome Canada
- Canadian Institute of Health Research
- Stand Up To Cancer Canada
- Canadian Registered Charity [80550 6730 RR0001]
- American Association for Cancer Research International -Canada
- Scientific Partner of SU2C Canada
- Paediatric Brain Tumour Foundation
- Terry Fox Research Institute [1087]
- Canadian Institutes of Health Research
- Cure Search Foundation
- Genome BC
- Genome Quebec
- Ontario Research Fund
- Worldwide Cancer Research, V-Foundation for Cancer Research
- Canadian Cancer Society Research Institute Impact grant
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- FRQS and Reseau de Medecine Genetique Appliquee
- We Love You Connie Foundation
- Cancer Prevention Research Institute of Texas (CPRIT) Scholar in Cancer Research award [RR170023]
- Alex's Lemonade Stand Foundation (ALSF) A award
- Nicole et Francois Angers Sarcoma Research Chair from the MGH Foundation, C17 Ewing Sarcoma Grant
- NATIONAL CANCER INSTITUTE [P01CA196539] Funding Source: NIH RePORTER
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Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1(+) osteoblast-like progenitor population toward an ACTA2(+) myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.
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