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

Nature Genetics volume 48, pages 273–282 (2016)Cite this article

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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.

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Figure 1: Recurrent rearrangement involving MYB and QKI in angiocentric gliomas.
Figure 2: Alterations of MYB and QKI occur frequently in human cancers.
Figure 3: MYB-QKI fusion protein functions as a transcription factor, and its molecular effects are observed in angiocentric gliomas.
Figure 4: Angiocentric gliomas exhibit aberrant expression of MYB-QKI due to H3K27ac-associated enhancer translocation and an autoregulatory feedback circuit in which MYB-QKI binds to the MYB promoter.
Figure 5: Human angiocentric gliomas exhibit the translocation of H3K27ac-marked enhancers with an aberrant enhancer associated with the MYB promoter.
Figure 6: MYB-QKI fusion protein and truncated MYB are oncogenic.
Figure 7: MYB-QKI rearrangement disrupts expression of QKI, a tumor-suppressor gene.
Figure 8: MYB-QKI rearrangement contributes to oncogenesis through at least three mechanisms.

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Acknowledgements

We thank and acknowledge the Dana-Farber Harvard Cancer Center/Pediatric Low-Grade Astrocytoma Consortium and the Children's Brain Tumor Tissue Consortium, including additional participating sites: Ann and Robert Lurie Children's Hospital, Seattle Children's Hospital and Children's Hospital of Pittsburgh for sample contribution, members of the Genomic Platform and Firehose Team at the Broad Institute for assistance with genomic sequencing and analysis, the Neuro-Histology laboratories of Boston Children's Hospital and Brigham and Women's Hospital, H. Homer (Brigham and Women's Hospital) for technical assistance with FISH, and members of the Ligon, Resnick and Beroukhim laboratories for useful discussions.

We acknowledge the following funding sources: A Kids' Brain Tumor Cure Foundation Pediatric Low-Grade Astrocytoma Foundation (P.B., K.L.L., R.B., M.W.K., L.G., C.D.S. and A.C.R.), US National Institutes of Health grant R01NS085336 (A.C.R., A.J.W., P.B.S. and M. Santi), Voices Against Brain Cancer (A.C.R.), the Children's Brain Tumor Foundation (A.C.R. and A.J.W.), the Stop and Shop Pediatric Brain Tumor Program (P.B. and M.W.K.), the Path to Cure Foundation (K.L.L.), US National Institutes of Health grant PO1CA142536 (C.D.S., K.L.L. and R.B.), St. Baldrick's Foundation (P.B.), the American Brain Tumor Association (L.A.R.), the Team Jack Foundation (P.B., M.W.K., R.B. and L.G.), the Andrysiak Fund for LGG (M.W.K.), a Broad Institute Scientific Projects to Accelerate Research and Collaboration (SPARC) grant (A.G.), the Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research (P.B., R.B. and S. Santagata), the Sontag Foundation (K.L.L. and R.B.), the Nuovo-Soldati Foundation (G.B.), the Philippe Foundation (G.B.), Fondation Etoile de Martin (J.G.), the Damon Runyon-Sohn Pediatric Fellowship Award (A.J.W.), a Hyundai Scholar Grant (A.J.W.), the Bear Necessities Pediatric Cancer Foundation (A.J.W. and A.C.R.), the Rally Foundation for Childhood Cancer Research (A.J.W.), National Institute of Neurological Disorders and Stroke (NINDS) grant K08NS087118 (S.H.R.), the Pediatric Brain Tumor Foundation (R.B. and P.B.), Thea's Star of Hope (A.C.R. and A.J.W.), the Hungarian Brain Research Program, grant KTIA_13_NAP-A-V/3, the Janos Bolyai Scholarship of the Hungarian Academy of Sciences (A.K.), NINDS grant 1R01NS091620 (D.A.H.-K.), the Nancy and Stephen Grand Philanthropic Fund (D.A.H.-K.) and the Pediatric Low-Grade Astrocytoma Foundation (D.A.H.-K.).

Finally, we thank and acknowledge the many children and families affected by PLGGs for their generous contributions to this research.

Author information

Author notes

  1. Pratiti Bandopadhayay, Lori A Ramkissoon, Payal Jain and Guillaume Bergthold: These authors contributed equally to this work.

  2. Keith L Ligon, Rameen Beroukhim and Adam C Resnick: These authors jointly supervised this work.

Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Pratiti Bandopadhayay, Guillaume Bergthold, Jeremiah Wala, Steven E Schumacher, Laura Urbanski, Ryan O'Rourke, William J Gibson, Brenton R Paolella, Peleg M Horowitz, Sandro Santagata, Charles D Stiles & Rameen Beroukhim

  2. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA

    Pratiti Bandopadhayay, Hayley Malkin, Liliana Goumnerova & Mark W Kieran

  3. Broad Institute, Cambridge, Massachusetts, USA

    Pratiti Bandopadhayay, Jeremiah Wala, Steven E Schumacher, Ryan O'Rourke, William J Gibson, Brenton R Paolella, Adam A Tracy, Sara Seepo, James E Bradner, Keith L Ligon & Rameen Beroukhim

  4. Harvard Medical School, Boston, Massachusetts, USA

    Pratiti Bandopadhayay, Jeremiah Wala, Rhamy Zeid, William J Gibson, Brenton R Paolella, Alexander Federation & Mark W Kieran

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Lori A Ramkissoon, Rhamy Zeid, Kristine Pelton, Shakti H Ramkissoon, Amanda Silva, Yun Jee Kang, David Knoff, Alexander Federation, James E Bradner, Keith L Ligon & Rameen Beroukhim

  6. Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Payal Jain, Harry J Han, Yuankun Zhu, Namrata Choudhari, Amanda Silva, Katie Boucher, Rosemary E Henn, Phillip B Storm & Adam C Resnick

  7. Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Payal Jain, Harry J Han, Yuankun Zhu, Namrata Choudhari, Amanda Silva, Katie Boucher, Rosemary E Henn, Phillip B Storm & Adam C Resnick

  8. Cell and Molecular Biology Graduate Group, Gene Therapy and Vaccines Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Payal Jain

  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

    Guillaume Bergthold & Jacques Grill

  10. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Shakti H Ramkissoon, Matthew Ducar, Sandro Santagata & Keith L Ligon

  11. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA

    Shakti H Ramkissoon, Sandro Santagata & Keith L Ligon

  12. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Shakti H Ramkissoon, Sandro Santagata & Keith L Ligon

  13. Broad Technology Laboratories, Broad Institute, Cambridge, Massachusetts, USA

    Adrianne Gladden-Young & Alon Goren

  14. Laboratoire de Neuropathologie, Hopital Sainte-Anne, Université Paris V Descartes, Paris, France

    Pascale Varlet & Melanie Pages

  15. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Peleg M Horowitz

  16. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Matthew Ducar & Paul Van Hummelen

  17. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Mariarita Santi

  18. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Mariarita Santi

  19. Pathology Unit, Anna Meyer Children's University Hospital, Florence, Italy

    Anna Maria Buccoliero

  20. Neurosurgery Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy

    Mirko Scagnet

  21. Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, Texas, USA

    Daniel C Bowers

  22. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

    Caterina Giannini

  23. Departement de Neurochirurgie, Hopital Necker–Enfants Malades, Université Paris V Descartes, Paris, France

    Stephanie Puget

  24. Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Cynthia Hawkins

  25. Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Uri Tabori

  26. Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Almos Klekner & Laszlo Bognar

  27. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Peter C Burger, Charles Eberhart & Fausto J Rodriguez

  28. Brain Tumor Institute, Children's National Medical Center, Washington, DC, USA

    D Ashley Hill

  29. Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Medical Center, Washington, DC, USA

    D Ashley Hill

  30. Department of Pathology, Children's National Medical Center, Washington, DC, USA

    D Ashley Hill

  31. Department of Neurology, University of California San Francisco School of Medicine, San Francisco, California, USA

    Sabine Mueller

  32. Department of Neurological Surgery, University of California San Francisco School of Medicine, San Francisco, California, USA

    Sabine Mueller, Daphne A Haas-Kogan & Joanna J Phillips

  33. Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, California, USA

    Sabine Mueller

  34. Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco School of Medicine, San Francisco, California, USA

    Daphne A Haas-Kogan

  35. Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA

    Daphne A Haas-Kogan

  36. Department of Pathology, University of California San Francisco, San Francisco, California, USA

    Joanna J Phillips

  37. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    James E Bradner & Rameen Beroukhim

  38. Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada

    Nada Jabado

  39. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    Nada Jabado

  40. Department of Pediatrics, McGill University, Montreal, Quebec, Canada

    Nada Jabado

  41. Brigham and Women's Hospital Department of Pathology, Division of Cytogenetics, Center for Advanced Molecular Diagnostics, Boston, Massachusetts, USA

    Azra H Ligon

  42. Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA

    Liliana Goumnerova

  43. Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA

    Liliana Goumnerova

  44. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Angela J Waanders

  45. Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Angela J Waanders, Phillip B Storm & Adam C Resnick

  46. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Angela J Waanders

  47. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Adam C Resnick

  48. Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Angela J Waanders, Phillip B Storm & Adam C Resnick

  49. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Rameen Beroukhim

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  1. Pratiti Bandopadhayay
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  2. Lori A Ramkissoon
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Contributions

P.B., L.A.R., P.J., G.B., K.L.L., R.B. and A.C.R. designed research. P.B., L.A.R., P.J., G.B., H.J.H., Y.Z., N.C., A.S., K.B., R.E.H., M. Santi, A.M.B., M. Scagnet, S.M., D.A.H., J.J.P., A.J.W., P.B.S., J.W., R.Z., S.E.S., L.U., R.O'R., W.J.G., K.P., S.H.R., Y.J.K., D.K., B.R.P., A.G.-Y., P.M.H., A.F., H.M., A.A.T., S. Seepo, M.D., P.V.H., D.C.B., S.P., C.H., U.T., A.K., L.B., P.C.B., C.E., F.J.R., D.A.H., D.A.H.-K., S. Santagata, C.D.S., J.E.B., N.J., A.G., J.G., A.H.L., L.G., M.W.K., K.L.L., R.B. and A.C.R. completed the research. P.B., L.A.R., P.J., G.B., J.W., H.J.H., Y.Z., A.J.W., P.B.S., R.Z., A.F., S.E.S., W.J.G., S.H.R., S. Santagata, A.G., J.E.B., A.H.L., A.C.R., K.L.L. and R.B. analyzed the data. J.W., P.V., M.P., D.C.B., C.G., S.P., C.H., U.T., A.K., L.B., P.C.B., C.E., M. Santi, A.M.B., M. Scagnet, S.M., D.A.H., D.A.H.-K., J.J.P., F.J.R., S. Santagata, N.J., A.G., J.G., A.H.L. and L.G. contributed new reagents, algorithms and/or samples. P.B., L.A.R., P.J., G.B., K.L.L., R.B. and A.C.R. wrote the manuscript. K.L.L., R.B. and A.C.R. supervised the study. All authors reviewed, edited and approved the manuscript.

Corresponding authors

Correspondence to Keith L Ligon, Rameen Beroukhim or Adam C Resnick.

Ethics declarations

Competing interests

The Dana-Farber Cancer Institute has licensed drug-like derivatives of JQ1 prepared in the Bradner laboratory to Tensha Therapeutics for clinical translation as cancer therapeutics. The Dana-Farber Cancer Institute and J.E.B. have been provided minor equity shares in Tensha Therapeutics.

Integrated supplementary information

Supplementary Figure 1 Significant regions of recurrent copy number alterations in PLGG.

GISTIC q values for amplifications (left) and deletions (right) are plotted across the genome.

Supplementary Figure 2 Driver genomic alterations in PLGGs.

Co-mutation plot of the driver alterations identified in 54 PLGGs profiled with WES and/or array CGH.

Supplementary Figure 3 MYB-QKI binding and transcriptional effects.

(a) Identified MYB-QKI binding peaks at MYB in mNSCs over-expressing MYB-QKI. (b) Expression of MYB, truncated MYB, MYB-QKI and truncated QKI in the cell lines used in mim-1 promoter assays. (c) Linear increases in mim-1 promoter activity with increases in MYB-QKI expression. (d) Enrichment of MYB pathway activation in normal brain, PLGGs without MYB-QKI and angiocentric gliomas with MYB-QKI. Values represent mean expression ± s.e.m.

Supplementary Figure 4 H3K27ac enhancer profiling of the 3′ region of QKI in a human angiocentric glioma.

H3K27ac enhancer peaks are associated with QKI in angiocentric glioma.

Supplementary Figure 5 H3K27ac enhancer formation at MYB in PLGGs.

H3K27ac enhancer formation at the MYB promoter in two human MYB-QKI angiocentric gliomas (top tracks) and a BRAF-altered pilocytic astrocytoma (lower track).

Supplementary Figure 6 Expression of MYB-QKI in HEK293T, NIH3T3 and mNSCs.

(a) MYB promoter activation in HEK293T and NIH3T3 cells with and without expression of MYB-QKI. (b) Exogenous expression of MYB-QKI and truncated MYB in NIH3T3 cells and mNSCs via retroviral transduction. (c) Representative OLIG2 and GFAP immunohistochemical analysis of tumors from mNSCs overexpressing truncated MYB, MYBQKI5 and MYB-QKI as compared to eGFP controls. Positive staining for both OLIG2 and GFAP is observed in a subset of tumor cells in tumors generated from truncated MYB or MYB-QKI5 overexpression, whereas tumors formed by MYB-QKI6 overexpression are negative for OLIG2 and have low levels of GFAP expression. Scale bars, 50 microns.

Supplementary Figure 7 Oncogenic activity of MYB-QKI.

(a) Number of colonies of NIH3T3 cells expressing MYB, MYB-QKI or a vector control in soft agar (left) and representative images (right). NIH3T3 cells overexpressing BRAF-V600E are shown as a positive control. The mean of three replicate measurements is shown. Error bars, s.e.m. (b) Table of tumor penetrance from both NIH3T3 and mNSC models with overall P < 0.001.

Supplementary Figure 8 Suppression of wild-type Qk in mouse neural stem cells expressing MYB-QKI.

(a) Suppression of wild-type Qk in mouse NSCs expressing MYB-QKI following infection with shQKI vectors (or shLacZ control). (b) Proliferation of mNSCs overexpressing eGFP, truncated MYB or MYB-QKI with suppression of wild-type Qk over 5 d in pool 4 (values represent the means of five replicate measurements with s.e.m.). Expression of wild-type Qk relative to shLacZ control is shown. (c) shQk signature defined following suppression of wild-type Qk in mNSCs that overexpress MYB-QKI6.

Supplementary Figure 9 MYB ChIP-seq binding to MYB target genes.

Binding of MYB to MYB target genes in K562 cells using the Abcam 45150 antibody.

Supplementary Figure 10 Validation of MYB ChIP-seq data.

(a) Top four enriched DNA-binding motifs in MYB ChIP-seq peaks obtained from mNSCs overexpressing MYB-QKI. (b) MYB DNA-binding motifs. (c) Venn diagrams showing overlap of the MYB-QKI peaks identified (P-value threshold = 1 × 10–6) as compared to those reported in Zhao et al. and Quintana et al. The P values shown were calculated by χ2 test with Yates correction. Of 2,879 genes identified in our set, 20% (Zhao) and 42% (Quintana) were also identified in the other studies.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Note. (PDF 1378 kb)

Supplementary Table 1

PLGGs included in analysis, including tumor demographics, method of profiling and driver alterations identified (XLSX 28 kb)

Supplementary Table 2

GISTIC amplification peaks (TXT 4 kb)

Supplementary Table 3

GISTIC deletion peaks (TXT 1 kb)

Supplementary Table 4

Differentially expressed genes in neural stem cells expressing eGFP, MYBtr or MYB-QKI (XLSX 6262 kb)

Supplementary Table 5

Gene-Set Enrichment Analysis in neural stem cells expressing eGFP, MYBtr or MYB-QKI (XLS 344 kb)

Supplementary Table 6

Differentially expressed genes in neural stem cells expressing MYB-QKI with shLacZ or shQk (XLSX 3420 kb)

Supplementary Table 7

miRNAs that are differentially expressed in mNSCs expressing MYB-QKI following suppression of wild type Qk (XLSX 37 kb)

Supplementary Table 8

MYB promoter sequence and shQk clones used in experiments (XLSX 21 kb)

Supplementary Table 9

PCR primers used in experiments (XLSX 41 kb)

Supplementary Table 10

ChIP-seq peaks (P = 1.0 × 10-6) identified following MYB ChIPseq in mNSC over-expressing MYBQKI5. Peaks that contain a MYB binding motif (fragment size used in analysis = 200 bp) are shown in the columns labeled MYBL1 or MYB (XLS 2137 kb)

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Bandopadhayay, P., Ramkissoon, L., Jain, P. et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48, 273–282 (2016). https://doi.org/10.1038/ng.3500

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