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Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2 activation

ALK and ROS1 fusions are key drivers of infant-type hemispheric gliomas (IHG). With diverse gene partners, the impact of ALK and ROS1 oncoprotein heterogeneity on glioma biology remains unknown. We developed an integrative phospho-proteomic and transcriptomic approach to discover biological function...

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Main Authors: Postlmayr, Andreas (Author) , Sanchez Bergman, Astrid (Author) , Torrejon Diaz, Jacob (Author) , Ciraulo, Bernard (Author) , Yan, Shen (Author) , Hofmann, Nina (Author) , Carbajal, Samanta (Author) , Dobler, Rosalie (Author) , Machaalani, Charbel (Author) , Schönholzer, Marc T. (Author) , Priego Gonzalez, Laura (Author) , De Micheli, Andrea J. (Author) , Berenjeno-Correa, Ernesto (Author) , Baroncini, Luca (Author) , Grotzer, Michael A. (Author) , Tabori, Uri (Author) , Hawkins, Cynthia (Author) , Ayrault, Olivier (Author) , Zuckermann, Marc (Author) , Baumgartner, Martin (Author) , Guerreiro Stücklin, Ana S. (Author)
Format: Article (Journal)
Language:English
Published: 5 March 2026
In: Cell reports
Year: 2026, Volume: 45, Issue: 3, Pages: 1-26
ISSN:2211-1247
DOI:10.1016/j.celrep.2026.117046
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.celrep.2026.117046
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Author Notes:Andreas Postlmayr, Astrid Sanchez Bergman, Jacob Torrejon Diaz, Bernard Ciraulo, Shen Yan, Nina Hofmann, Samanta Carbajal, Rosalie Dobler, Charbel Machaalani, Marc T. Schönholzer, Laura Priego Gonzalez, Andrea J. De Micheli, Ernesto Berenjeno-Correa, Luca Baroncini, Michael A. Grotzer, Uri Tabori, Cynthia Hawkins, Olivier Ayrault, Marc Zuckermann, Martin Baumgartner, Ana S. Guerreiro Stücklin
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Summary:ALK and ROS1 fusions are key drivers of infant-type hemispheric gliomas (IHG). With diverse gene partners, the impact of ALK and ROS1 oncoprotein heterogeneity on glioma biology remains unknown. We developed an integrative phospho-proteomic and transcriptomic approach to discover biological functions regulated by five IHG-associated fusions: CCDC88A::ALK, PPP1CB::ALK, GOPC::ROS1, CLIP1::ROS1, and KIF21A::ROS1. Here, we report fusion-specific oncogenic functions conferred by the 5' gene partner, including increased cell motility driven by microtubule-interacting fusions CCDC88A::ALK and CLIP1::ROS1. All studied fusions converge on STAT3 activation. Using affinity purification mass spectrometry, we identified SHP2 in direct interaction with all three ROS1 oncoproteins but with none of the ALK oncoproteins, which in turn interact with SHC1/SHC3. ROS1 fusions phosphorylate SHP2 to a greater extent than ALK fusions, and analyses of downstream pathways suggest MAPK-independent, non-canonical SHP2-driven functions. Our findings reveal both common and fusion-specific dependencies, offering opportunities to optimize therapeutic strategies for pediatric gliomas.
Item Description:Gesehen am 10.06.2026
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2026.117046

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