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

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 KnoffBrenton 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

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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.

Original language	English
Pages (from-to)	273-282
Number of pages	10
Journal	Nature Genetics
Volume	48
Issue number	3
DOIs	https://doi.org/10.1038/ng.3500
Publication status	Published - 1 Mar 2016
Externally published	Yes

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Bandopadhayay, P., Ramkissoon, L. A., Jain, P., Bergthold, G., Wala, J., Zeid, R., Schumacher, S. E., Urbanski, L., O'Rourke, R., Gibson, W. J., Pelton, K., Ramkissoon, S. H., Han, H. J., Zhu, Y., Choudhari, N., Silva, A., Boucher, K., Henn, R. E., Kang, Y. J., ... Resnick, A. C. (2016). MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nature Genetics, 48(3), 273-282. https://doi.org/10.1038/ng.3500

@article{35de54a052a44432b159512c55076091,

title = "MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = mar,

day = "1",

doi = "10.1038/ng.3500",

language = "English",

volume = "48",

pages = "273--282",

journal = "Nature Genetics",

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Bandopadhayay, P, Ramkissoon, LA, Jain, P, Bergthold, G, Wala, J, Zeid, R, Schumacher, SE, Urbanski, L, O'Rourke, R, Gibson, WJ, Pelton, K, Ramkissoon, SH, Han, HJ, Zhu, Y, Choudhari, N, Silva, A, Boucher, K, Henn, RE, Kang, YJ, Knoff, D, Paolella, BR, Gladden-Young, A, Varlet, P, Pages, M, Horowitz, PM, Federation, A, Malkin, H, Tracy, AA, Seepo, S, Ducar, M, Van Hummelen, P, Santi, M, Buccoliero, AM, Scagnet, M, Bowers, DC, Giannini, C, Puget, S, Hawkins, C, Tabori, U, Klekner, A, Bognar, L, Burger, PC, Eberhart, C, Rodriguez, FJ, Hill, DA, Mueller, S, Haas-Kogan, DA, Phillips, JJ, Santagata, S, Stiles, CD, Bradner, JE, Jabado, N, Goren, A, Grill, J, Ligon, AH, Goumnerova, L, Waanders, AJ, Storm, PB, Kieran, MW, Ligon, KL, Beroukhim, R & Resnick, AC 2016, 'MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism', Nature Genetics, vol. 48, no. 3, pp. 273-282. https://doi.org/10.1038/ng.3500

TY - JOUR

T1 - MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

AU - Bandopadhayay, Pratiti

AU - Ramkissoon, Lori A.

AU - Jain, Payal

AU - Bergthold, Guillaume

AU - Wala, Jeremiah

AU - Zeid, Rhamy

AU - Schumacher, Steven E.

AU - Urbanski, Laura

AU - O'Rourke, Ryan

AU - Gibson, William J.

AU - Pelton, Kristine

AU - Ramkissoon, Shakti H.

AU - Han, Harry J.

AU - Zhu, Yuankun

AU - Choudhari, Namrata

AU - Silva, Amanda

AU - Boucher, Katie

AU - Henn, Rosemary E.

AU - Kang, Yun Jee

AU - Knoff, David

AU - Paolella, Brenton R.

AU - Gladden-Young, Adrianne

AU - Varlet, Pascale

AU - Pages, Melanie

AU - Horowitz, Peleg M.

AU - Federation, Alexander

AU - Malkin, Hayley

AU - Tracy, Adam A.

AU - Seepo, Sara

AU - Ducar, Matthew

AU - Van Hummelen, Paul

AU - Santi, Mariarita

AU - Buccoliero, Anna Maria

AU - Scagnet, Mirko

AU - Bowers, Daniel C.

AU - Giannini, Caterina

AU - Puget, Stephanie

AU - Hawkins, Cynthia

AU - Tabori, Uri

AU - Klekner, Almos

AU - Bognar, Laszlo

AU - Burger, Peter C.

AU - Eberhart, Charles

AU - Rodriguez, Fausto J.

AU - Hill, D. Ashley

AU - Mueller, Sabine

AU - Haas-Kogan, Daphne A.

AU - Phillips, Joanna J.

AU - Santagata, Sandro

AU - Stiles, Charles D.

AU - Bradner, James E.

AU - Jabado, Nada

AU - Goren, Alon

AU - Grill, Jacques

AU - Ligon, Azra H.

AU - Goumnerova, Liliana

AU - Waanders, Angela J.

AU - Storm, Phillip B.

AU - Kieran, Mark W.

AU - Ligon, Keith L.

AU - Beroukhim, Rameen

AU - Resnick, Adam C.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84959547851&partnerID=8YFLogxK

U2 - 10.1038/ng.3500

DO - 10.1038/ng.3500

M3 - Article

C2 - 26829751

AN - SCOPUS:84959547851

SN - 1061-4036

VL - 48

SP - 273

EP - 282

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

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