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H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone

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H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone Published OnlineFirst September 23, 2020; DOI: 10.1158/2159-8290.CD-20-0461 RESEARCH ARTICLE H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone Sima Khazaei1, Nicolas De Jay1,2, Shriya Deshmukh3, Liam D. Hendrikse4,5,6, Wajih Jawhar1,7, Carol C.L. Chen1, Leonie G. Mikael8, Damien Faury8, Dylan M. Marchione9, Joel Lanoix10, Éric Bonneil10, Takeaki Ishii7,11, Siddhant U. Jain12, Kateryna Rossokhata1, Tianna S. Sihota1, Robert Eveleigh13, Véronique Lisi1, Ashot S. Harutyunyan8, Sungmi Jung14, Jason Karamchandani15, Brendan C. Dickson16, Robert Turcotte17, Jay S. Wunder18,19, Pierre Thibault10,20, Peter W. Lewis12, Benjamin A. Garcia9, Stephen C. Mack21, Michael D. Taylor4,5,6, Livia Garzia7,17, Claudia L. Kleinman1,2, and Nada Jabado1,3,8 Illustration by Bianca Dunn by Illustration Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst September 23, 2020; DOI: 10.1158/2159-8290.CD-20-0461 ABSTRACT 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 profi ling 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 + myofi broblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our fi ndings 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 epi- genetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interac- tions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT. See related commentary by Licht, p. 1794. INTRODUCTION tion of glycine 34 to tryptophan or, more rarely, to leucine (G34W/L, >92% of cases; ref. 2 ). Unlike H3.3 glycine 34-to- Giant cell tumor of bone (GCT) is a locally aggressive arginine or valine substitutions (H3.3 G34R/V) that arise yet rarely metastasizing neoplasm that accounts for 20% of in brain tumors and co-occur with partner TP53 and ATRX benign bone tumors ( 1 ). Tumors are composed of three major mutations ( 3, 4 ), H3.3 G34W/L mutations are the only recur- compartments: multinucleated osteoclast-like giant cells, rent molecular alteration in GCT, potentially driving this macrophage-like monocytes, and stromal cells. Although destructive bone disease ( 2, 5 ). the primary cause of morbidity in GCT is bone resorption Although the almost universal occurrence of H3.3 G34W/L by monocyte-derived giant osteoclasts, the actual neoplastic mutations in GCT (92%) strongly suggests a causal role, how component is formed by cells from the poorly defi ned mes- these mutations drive tumorigenesis in the bone remains enchymal stromal compartment, which bears heterozygous unknown. Moreover, the cellular processes that result in somatic mutations in H3F3A , one of two genes encoding multinucleated giant cell recruitment have yet to be eluci- histone 3 variant H3.3 ( 2 ). These mutations lead to substitu- dated. Other H3 mutations, highly recurrent in a wide range 1 Department of Human Genetics, McGill University, Montreal, Quebec, Orthopaedic Surgery, McGill University, Montreal, Quebec, Canada. 18 Uni- Canada. 2 Lady Davis Research Institute, Jewish General Hospital, Mon- versity of Toronto Musculoskeletal Oncology Unit, Mount Sinai Hospital, treal, Quebec, Canada. 3 Department of Experimental Medicine, McGill Toronto, Ontario, Canada. 19 Department of Surgical Oncology, Princess University, Montreal, Quebec, Canada. 4 Cancer and Stem Cell Biology Margaret Cancer Centre, Toronto, Ontario, Canada. 20 Department of Chem- Program, The Hospital for Sick Children, Toronto, Ontario, Canada. 5 The istry, Université de Montréal, Montreal, Quebec, Canada. 21 Department of Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Pediatrics, Division of Hematology and Oncology, Texas Children’s Cancer Sick Children, Toronto, Ontario, Canada. 6 Department of Medical Biophys- and Hematology Centers, Dan L. Duncan Cancer Center, Baylor College of ics, University of Toronto, Toronto, Ontario, Canada. 7 Cancer Research Medicine, Houston, Texas. Program, The Research Institute of the McGill University Health Centre, Note: Supplementary data for this article are available at Cancer Discovery 8 Montreal, Quebec, Canada. Department of Pediatrics, McGill Univer- Online (http://cancerdiscovery.aacrjournals.org/). sity, and The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada. 9 Department of Biochemistry and Biophysics, S. Khazaei, N. De Jay, S. Deshmukh, and L.D. Hendrikse contributed equally and Penn Epigenetics Institute, Perelman School of Medicine, University to this article. of Pennsylvania, Philadelphia, Pennsylvania. 10 Institute for Research in Corresponding Authors: Nada Jabado , Montreal University Hospital/McGill Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, University Health Centre, 1001 Décarie Boulevard, Montreal, Quebec H4A Canada. 11 Department of Experimental Surgery, McGill University, Mon- 3J1, Canada. Phone: 514-934-1934, ext. 76163; Fax: 514-412-4331; treal, Quebec, Canada. 12 Department of Biomolecular Chemistry, School E-mail: [email protected]; and Claudia Kleinman, Lady Davis Institute of Medicine and Public Health and Wisconsin Institute for Discovery, Uni- for Medical Research, 3999 Côte Ste-Catherine Road, Montreal, Que- versity of Wisconsin, Madison, Wisconsin. 13 McGill University and Génome bec H3T 1E2, Canada. Phone: 514-340-8222, ext. 26129; E-mail: claudia. Québec Innovation Centre, Montreal, Quebec, Canada. 14 Department of [email protected] Pathology, McGill University Health Centre, Montreal, Quebec, Canada. Cancer Discov 2020;10:1968–87 15 Department of Pathology, Montreal Neurological Institute, McGill Uni- versity, Montreal, Quebec, Canada. 16 Department of Pathology and Labo- doi: 10.1158/2159-8290.CD-20-0461 ratory Medicine, Mt. Sinai Hospital, Toronto, Ontario, Canada. 17 Division of © 2020 American Association for Cancer Research. December 2020 CANCER DISCOVERY | 1969 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst September 23, 2020; DOI: 10.1158/2159-8290.CD-20-0461 RESEARCH ARTICLE Khazaei et al. of cancers, affect residues that are direct targets of post- been mainly restricted to overexpression systems that translational modifications (PTM). These lysine to methio- increase mutant histone expression beyond that observed nine substitutions on K27 (K27M) and K36 (K36M) of the H3 in tumors (15, 20). However, accounting for dosage is key, tail impair enzymatic activities of the corresponding methyl- because oncohistones contribute to less than 20% of the transferases (6). This results in genome-wide changes in the total H3 pool (6). To address these challenges, we gener- deposition and distribution of major antagonistic repres- ated H3.3 G34W (referred to hereafter as G34W) isogenic sive (H3K27me3) or activating (H3K36me3, H3K36me2, models using CRISPR–Cas9 in patient-derived GCT stro- H3K27ac) chromatin marks, and redistribution of the mal cells as well as patient-derived orthotopic xenografts repressive polycomb receptor complex (PRC) 1 and 2 to (PDOX). We profiled the epigenome, transcriptome, and promote aberrant transcription and tumorigenesis (7–13). secreted Golgi proteome of cellular models, and generated In contrast, H3.3G34 mutations are less well understood. transcriptomic data of GCT primary tumors and PDOX at They exclusively affect noncanonical H3.3 histones, sug- single-cell resolution. Our combined modeling and profil- gesting an underinvestigated H3.3-dependent role in their ing efforts shed light on the mechanism by which G34W tumorigenesis. Indeed, deposition of H3.3 is replication- transforms cells to promote tumorigenicity and enables independent and follows a specific temporospatial pattern interactions with the tumor microenvironment (TME) of that may be relevant to GCT formation. H3.3 marks active the bone to foster disease. euchromatin at enhancers and gene bodies, but also rep- resents the main H3 variant in silent pericentromeric and RESULTS telomeric heterochromatin (14). The presence of mutant H3.3G34 could therefore affect chromatin locally in any G34W Is Required for Tumor Formation and of these key genomic regions, contributing to tumorigen- Promotes Osteoclast Recruitment in GCT esis. Although H3.3G34 mutations occur on a residue that To determine
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