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Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas.
Sweha, Stefan R; Chung, Chan; Natarajan, Siva Kumar; Panwalkar, Pooja; Pun, Matthew; Ghali, Amer; Bayliss, Jill; Pratt, Drew; Shankar, Anand; Ravikumar, Visweswaran; Rao, Arvind; Cieslik, Marcin; Wilder-Romans, Kari; Scott, Andrew J; Wahl, Daniel R; Jessa, Selin; Kleinman, Claudia L; Jabado, Nada; Mackay, Alan; Jones, Chris; Martinez, Daniel; Santi, Mariarita; Judkins, Alexander R; Yadav, Viveka Nand; Qin, Tingting; Phoenix, Timothy N; Koschmann, Carl J; Baker, Suzanne J; Chinnaiyan, Arul M; Venneti, Sriram.
Afiliação
  • Sweha SR; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Chung C; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
  • Natarajan SK; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Panwalkar P; Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.
  • Pun M; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Ghali A; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Bayliss J; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Pratt D; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Shankar A; Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Ravikumar V; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Rao A; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Cieslik M; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Wilder-Romans K; Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Scott AJ; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Wahl DR; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Jessa S; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Kleinman CL; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Jabado N; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mackay A; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Jones C; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Martinez D; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Santi M; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Judkins AR; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Yadav VN; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Qin T; Quantitative Life Sciences, McGill University, Montreal, Quebec H3A 2A7, Canada.
  • Phoenix TN; Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
  • Koschmann CJ; Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
  • Baker SJ; Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada.
  • Chinnaiyan AM; Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada.
  • Venneti S; Department of Pediatrics, McGill University, and Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Sci Transl Med ; 13(615): eabf7860, 2021 Oct 13.
Article em En | MEDLINE | ID: mdl-34644147
ABSTRACT
High-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier­penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos