METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma.

Autor:	Thombare K; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden., Vaid R; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden., Pucci P; Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK., Ihrmark Lundberg K; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, and Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden., Ayyalusamy R; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden., Baig MH; Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-Ro, Gangnam-Gu, Seoul, 06273, Republic of Korea., Mendez A; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden., Burgos-Panadero R; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden., Höppner S; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany., Bartenhagen C; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany., Sjövall D; Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden., Rehan AA; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden., Dattatraya Nale S; BNJ Biopharma, Memorial Hall, 85, Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea., Djos A; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden., Martinsson T; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden., Jaako P; Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden., Dong JJ; Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-Ro, Gangnam-Gu, Seoul, 06273, Republic of Korea., Kogner P; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, and Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden., Johnsen JI; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, and Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden., Fischer M; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany., Turner SD; Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK., Mondal T; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. tanmoy.mondal@gu.se.; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden. tanmoy.mondal@gu.se.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Nov 11. Date of Electronic Publication: 2024 Nov 11.
DOI:	10.1038/s44318-024-00299-8
Abstrakt:	Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N 6 -methyladenosine (m 6 A) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the m 6 A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m 6 A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC. We demonstrate that the m 6 A modification regulates the expression of HOX genes in tNCC, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m 6 A modified in MYCN-amplified NB with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) in vivo, suggesting METTL3 inhibition could be a potential therapeutic approach for NB. Competing Interests: Disclosure and competing interests statement The authors declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
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