ALK positively regulates MYCN activity through repression of HBP1 expression.

Autor: Claeys S; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Denecker G; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Durinck K; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Decaesteker B; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Mus LM; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Loontiens S; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Vanhauwaert S; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Althoff K; Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany., Wigerup C; Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden., Bexell D; Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden., Dolman E; Princess Maxima Center for Pediatric Cancer, Utrecht, The Netherlands., Henrich KO; Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany., Wehrmann L; Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany., Westerhout EM; Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands., Demoulin JB; De Duve Institute, Université Catholique de Louvain, Brussels, Belgium., Kumps C; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Department of Uro-Gynaecology, Ghent University Hospital, Ghent, Belgium., Van Maerken T; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Laureys G; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Pediatric Oncology and Hematology, Ghent University Hospital, Ghent, Belgium., Van Neste C; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., De Wilde B; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Pediatric Oncology and Hematology, Ghent University Hospital, Ghent, Belgium., De Wever O; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Laboratory of Experimental Cancer Research (LECR), Ghent University, Ghent, Belgium., Westermann F; Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany., Versteeg R; Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands., Molenaar JJ; Princess Maxima Center for Pediatric Cancer, Utrecht, The Netherlands., Påhlman S; Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden., Schulte JH; Department of Pediatric Oncology/Hematology, Charite University Hospital Berlin, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.; German Translational Cancer Research Consortium (DKTK), Berlin, Germany.; German Translational Cancer Research Consortium (DKFZ), Heidelberg, Germany., De Preter K; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium., Speleman F; Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium. franki.speleman@ugent.be.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium. franki.speleman@ugent.be.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2019 Apr; Vol. 38 (15), pp. 2690-2705. Date of Electronic Publication: 2018 Dec 11.
DOI: 10.1038/s41388-018-0595-3
Abstrakt: ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the 'HMG-box transcription factor 1' (HBP1) through the PI 3 K-AKT-FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI 3 K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
Databáze: MEDLINE
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