MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

Pratiti Bandopadhayay; Lori A Ramkissoon; Payal Jain; Guillaume Bergthold; Jeremiah Wala; Rhamy Zeid; Steven E Schumacher; Laura Urbanski; Ryan O'Rourke; William J Gibson; Kristine Pelton; Shakti H Ramkissoon; Harry J Han; Yuankun Zhu; Namrata Choudhari; Amanda Silva; Katie Boucher; Rosemary E Henn; Yun Jee Kang; David Knoff; Brenton R Paolella; Adrianne Gladden-Young; Pascale Varlet; Melanie Pages; Peleg M Horowitz; Alexander Federation; Hayley Malkin; Adam A Tracy; Sara Seepo; Matthew Ducar; Paul Van Hummelen; Mariarita Santi; Anna Maria Buccoliero; Mirko Scagnet; Daniel C Bowers; Caterina Giannini; Stephanie Puget; Cynthia Hawkins; Uri Tabori; Almos Klekner; Laszlo Bognar; Peter C Burger; Charles Eberhart; Fausto J Rodriguez; D Ashley Hill; Sabine Mueller; Daphne A Haas-Kogan; Joanna J Phillips; Sandro Santagata; Charles D Stiles; James E Bradner; Nada Jabado; Alon Goren; Jacques Grill; Azra H Ligon; Liliana Goumnerova; Angela J Waanders; Phillip B Storm; Mark W Kieran; Keith L Ligon; Rameen Beroukhim; Adam C Resnick

doi:10.1038/ng.3500

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

Nat Genet. 2016 Mar;48(3):273-82. doi: 10.1038/ng.3500. Epub 2016 Feb 1.

Authors

Pratiti Bandopadhayay^{1

2

3

4}, Lori A Ramkissoon⁵, Payal Jain^{6

7

8}, Guillaume Bergthold^{1

9}, Jeremiah Wala^{1

3

4}, Rhamy Zeid^{4

5}, Steven E Schumacher^{1

3}, Laura Urbanski¹, Ryan O'Rourke^{1

3}, William J Gibson^{1

3

4}, Kristine Pelton⁵, Shakti H Ramkissoon^{5

10

11

12}, Harry J Han^{6

7}, Yuankun Zhu^{6

7}, Namrata Choudhari^{6

7}, Amanda Silva^{5

6

7}, Katie Boucher^{6

7}, Rosemary E Henn^{6

7}, Yun Jee Kang⁵, David Knoff⁵, Brenton R Paolella^{1

3

4}, Adrianne Gladden-Young¹³, Pascale Varlet¹⁴, Melanie Pages¹⁴, Peleg M Horowitz^{1

15}, Alexander Federation^{4

5}, Hayley Malkin², Adam A Tracy³, Sara Seepo³, Matthew Ducar^{10

16}, Paul Van Hummelen¹⁶, Mariarita Santi^{17

18}, Anna Maria Buccoliero¹⁹, Mirko Scagnet²⁰, Daniel C Bowers²¹, Caterina Giannini²², Stephanie Puget²³, Cynthia Hawkins²⁴, Uri Tabori²⁵, Almos Klekner²⁶, Laszlo Bognar²⁶, Peter C Burger²⁷, Charles Eberhart²⁷, Fausto J Rodriguez²⁷, D Ashley Hill^{28

29

30}, Sabine Mueller^{31

32

33}, Daphne A Haas-Kogan^{32

34

35}, Joanna J Phillips^{32

36}, Sandro Santagata^{1

10

11

12}, Charles D Stiles¹, James E Bradner^{3

5

37}, Nada Jabado^{38

39

40}, Alon Goren¹³, Jacques Grill⁹, Azra H Ligon⁴¹, Liliana Goumnerova^{2

42

43}, Angela J Waanders^{44

45

46

47}, Phillip B Storm^{6

7

45

47}, Mark W Kieran^{2

4}, Keith L Ligon^{3

5

10

11

12}, Rameen Beroukhim^{1

3

5

37

48}, Adam C Resnick^{6

7

45

49

47}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
³ Broad Institute, Cambridge, Massachusetts, USA.
⁴ Harvard Medical School, Boston, Massachusetts, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁶ Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁷ Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Cell and Molecular Biology Graduate Group, Gene Therapy and Vaccines Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department de Cancerologie de l'Enfant et de l'Adolescent et Unité Mixte de Recherche du Centre National de la Recherche Scientifique 8203 'Vectorologie et Nouvelles Therapeutiques du Cancer', Gustave Roussy, Université Paris XI Sud, Villejuif, France.
¹⁰ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹¹ Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹² Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
¹³ Broad Technology Laboratories, Broad Institute, Cambridge, Massachusetts, USA.
¹⁴ Laboratoire de Neuropathologie, Hopital Sainte-Anne, Université Paris V Descartes, Paris, France.
¹⁵ Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁶ Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁷ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁸ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Pathology Unit, Anna Meyer Children's University Hospital, Florence, Italy.
²⁰ Neurosurgery Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy.
²¹ Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, Texas, USA.
²² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
²³ Departement de Neurochirurgie, Hopital Necker-Enfants Malades, Université Paris V Descartes, Paris, France.
²⁴ Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁵ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁶ Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
²⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁸ Brain Tumor Institute, Children's National Medical Center, Washington, DC, USA.
²⁹ Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Medical Center, Washington, DC, USA.
³⁰ Department of Pathology, Children's National Medical Center, Washington, DC, USA.
³¹ Department of Neurology, University of California San Francisco School of Medicine, San Francisco, California, USA.
³² Department of Neurological Surgery, University of California San Francisco School of Medicine, San Francisco, California, USA.
³³ Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, California, USA.
³⁴ Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco School of Medicine, San Francisco, California, USA.
³⁵ Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
³⁶ Department of Pathology, University of California San Francisco, San Francisco, California, USA.
³⁷ Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
³⁸ Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada.
³⁹ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
⁴⁰ Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
⁴¹ Brigham and Women's Hospital Department of Pathology, Center for Advanced Molecular Diagnostics, Division of Cytogenetics, Boston, Massachusetts, USA.
⁴² Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA.
⁴³ Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA.
⁴⁴ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴⁵ Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴⁶ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁷ Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴⁸ Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁴⁹ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

PMID: 26829751
PMCID: PMC4767685
DOI: 10.1038/ng.3500

Abstract

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis / genetics
Cell Line, Tumor
Child
Comparative Genomic Hybridization
Exome / genetics
Gene Expression Regulation, Neoplastic
Gene Rearrangement
Glioma / genetics*
Glioma / pathology
High-Throughput Nucleotide Sequencing
Humans
Mutation
Oncogene Proteins v-myb / biosynthesis
Oncogene Proteins v-myb / genetics*
Oncogene Proteins, Fusion / biosynthesis
Oncogene Proteins, Fusion / genetics*
RNA-Binding Proteins / biosynthesis
RNA-Binding Proteins / genetics*

Substances

Oncogene Proteins v-myb
Oncogene Proteins, Fusion
QKI protein, human
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding