Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

Author:

Lu Chao1,Jain Siddhant U.23,Hoelper Dominik23,Bechet Denise4,Molden Rosalynn C.56,Ran Leili7,Murphy Devan7,Venneti Sriram8,Hameed Meera9,Pawel Bruce R.10,Wunder Jay S.1112,Dickson Brendan C.1314,Lundgren Stefan M.23,Jani Krupa S.6,De Jay Nicolas4,Papillon-Cavanagh Simon4,Andrulis Irene L.13141516,Sawyer Sarah L.17,Grynspan David17,Turcotte Robert E.18,Nadaf Javad4,Fahiminiyah Somayyeh4,Muir Tom W.6,Majewski Jacek4,Thompson Craig B.19,Chi Ping720,Garcia Benjamin A.5,Allis C. David1,Jabado Nada421,Lewis Peter W.23

Affiliation:

1. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.

2. Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA.

3. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.

4. Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.

5. Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

6. Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.

7. Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

8. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

9. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

10. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

11. University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

12. Department of Surgical Oncology and Division of Orthopedic Surgery, Princess Margaret Hospital, University of Toronto, Toronto, Ontario M5T 2M9, Canada.

13. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

14. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

15. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

16. The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.

17. Department of Medical Genetics and Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.

18. Division of Orthopaedic Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.

19. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

20. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

21. Department of Pediatrics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.

Abstract

An oncohistone deranges inhibitory chromatin Missense mutations (that change one amino acid for another) in histone H3 can produce a so-called oncohistone and are found in a number of pediatric cancers. For example, the lysine-36–to-methionine (K36M) mutation is seen in almost all chondroblastomas. Lu et al. show that K36M mutant histones are oncogenic, and they inhibit the normal methylation of this same residue in wild-type H3 histones. The mutant histones also interfere with the normal development of bone-related cells and the deposition of inhibitory chromatin marks. Science , this issue p. 844

Funder

Rockefeller University

Wisconsin Institute for Discovery

Greater Milwaukee Foundation

Starr Cancer Consortium

Sidney Kimmel Foundation

NIH

Cancer Center Support

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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