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

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

doi:10.1038/ng.3500

Cited by 245 publications

(237 citation statements)

References 67 publications

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“…[37][38][39][40] Recent next-generation sequencing studies have identified gene rearrangements of NTRK1, 2, and 3 encoding novel oncogenic fusions in a variety of tumor types, including low-grade and highgrade astrocytoma. 6,[15][16][17] The NTRK2 fusion gene was first identified in pilocytic astrocytoma, with recent reports of additional fusions including QKI-NTRK2, NACC2-NTRK2, VCL-NTRK2, AGBL4-NTRK2, TRIM24-NTRK2, PAN3-NTRK2, AFAP1-NTRK2, SQSTM1-NTRK2, NAV1-NTRK2, and SLMAP-NTRK2. 6,[15][16][17]41,42 The mechanism of action of these fusion proteins in human gliomagenesis, progression, and drug resistance remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…6,[15][16][17] The NTRK2 fusion gene was first identified in pilocytic astrocytoma, with recent reports of additional fusions including QKI-NTRK2, NACC2-NTRK2, VCL-NTRK2, AGBL4-NTRK2, TRIM24-NTRK2, PAN3-NTRK2, AFAP1-NTRK2, SQSTM1-NTRK2, NAV1-NTRK2, and SLMAP-NTRK2. 6,[15][16][17]41,42 The mechanism of action of these fusion proteins in human gliomagenesis, progression, and drug resistance remains poorly understood. In this study we performed a systematic screen of TK-TELs, which suggested that activated TrkB could transform Ink4a −/− /Arf −/− astrocytes in vivo via upregulation of pSTAT3 signaling and Ccl2 production.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, NTRK2 fusions are present in 2%-3% of low-grade and high-grade astrocytomas. 6,[15][16][17] We further demonstrated that one QKI-NTRK2 fusion mutant with clinical relevance in humans is a driver in astrocytoma, suggesting that NTRK2 fusions might serve as potential therapeutic targets.…”

Section: Neurooncologymentioning

confidence: 99%

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Tyrosine receptor kinase B is a drug target in astrocytomas

Xie

Ramkissoon

et al. 2016

Neuro-Oncology

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Background. Astrocytomas are the most common primary human brain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and lowgrade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type. Methods. To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a −/− /Arf −/− astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas. Results. Activated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with human astrocytoma transformed Ink4a −/− /Arf −/− astrocytes, and this process was also mediated via STAT3 signaling. Conclusions. Our findings provide evidence that constitutively activated NTRK2 alleles, notably the human tumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytoma patients defined by QKI-NTRK2 fusion. Key words astrocytoma | CCL2 | NTRK2 | STAT3 | QKI-NTRK2

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tyrosine receptor kinase B is a drug target in astrocytomas

Xie

Ramkissoon

et al. 2016

Neuro-Oncology

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“…QKI may also directly regulate SOX2 expression via specific binding to its mRNA 3 ′ UTR in a cis-element-dependent way . Recently, MYB-QKI fusions were identified as a specific and single candidate-driver event in angiocentric gliomas (Bandopadhayay et al 2016). In vitro and in vivo functional studies demonstrated 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 QKI tumor suppressor (Bandopadhayay et al 2016).…”

Section: Qki-quaking Kh Domain Containing Rna Bindingmentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

235

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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“…37 Additionally, alterations in MYB and MYBL1, primarily fusion events, have been observed in angiocentric gliomas and low-grade astrocytomas. 30,45 Clinical trials for targeted therapy addressing some of these various abnormalities are ongoing or in development. 30,46 Given the large number of diagnostic entities with overlapping histologic and molecular features in this category, the diagnostic approach is less algorithmic than for infiltrating gliomas.…”

Section: Poorly Infiltrative Glial and Glioneuronalmentioning

confidence: 99%

Genomic Analysis in the Practice of Surgical Neuropathology: The Emory Experience

Neill

Saxe

Rossi

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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The evaluation of central nervous system tumors increasingly relies on molecular genetic methods to aid in classification, offer prognostic information, and predict response to therapy. Available assays make it possible to assess genetic losses, amplifications, translocations, mutations, or the expression levels of specific gene transcripts or proteins. Current molecular diagnostics frequently use a panel-based approach and whole genome analysis, and generally rely either on DNA sequencing or on hybridization-based methodologies, such as those used in cytogenomic microarrays. In some cases, immunohistochemistry can be used as a surrogate for genetic analysis when the mutation of interest consistently results in overexpression or underexpression of a known protein product. In surgical neuropathology practice, the diagnostic workup of diffuse gliomas, medulloblastomas, low-grade circumscribed gliomas, as well as other diseases, now routinely incorporates the results of genomic studies. Here we summarize our institution's current approach to diagnostic surgical neuropathology, using these contemporary molecular diagnostic applications.

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

Cited by 245 publications

References 67 publications

Tyrosine receptor kinase B is a drug target in astrocytomas

Tyrosine receptor kinase B is a drug target in astrocytomas

Splicing-factor alterations in cancers

Genomic Analysis in the Practice of Surgical Neuropathology: The Emory Experience

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