KLF4 K409Q –mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Acta Neuropathologica Communications

Niklas von Spreckelsen¹  Christoph Kesseler¹  Natalie Waldt¹  Christian Mawrin¹  Elmar Kirches¹  Till Acker²  Hui-Ke Jiao²  Attila Nemeth²  Hildegard Dohmen²  Martina Deckert³  Stefan Schob⁴  Cordula Scherlach⁴  E. Antonio Chiocca⁵  Pantelis Stavrinou⁶  Marco Timmer⁶  Boris Krischek⁶  Roland Goldbrunner⁶  Ibrahim Erol Sandalcioglu⁷  Stefan Huettelmaier⁸  Rebecca Poetschke⁸  Frank Angenstein⁹  Marc Remke^1,10 

[1] Department of Neuropathology, Otto-von-Guericke University;Department of Neuropathology, University Giessen;Department of Neuropathology, University Hospital Cologne;Department of Neuroradiology, University Hospital Leipzig;Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School;Department of Neurosurgery, Center for Neurosurgery, Faculty of Medicine and University Hospital, University of Cologne;Department of Neurosurgery, Otto-von-Guericke University;Institute of Molecular Medicine, Martin Luther University;Laboratory for Non-invasive Imaging, DZNE;Pediatric Neuro-Oncology;

关键词: Meningioma;    Mutation;    K409Q;    Hypoxia;    HIF;    Edema;   

DOI  :  10.1186/s40478-020-00912-x

来源: DOAJ

【 摘 要 】

Abstract Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

【 授权许可】

Unknown