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

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 b...

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Veröffentlicht in:The EMBO journal 2024-11, Vol.43 (24), p.6310-6335
Hauptverfasser: Thombare, Ketan, Vaid, Roshan, Pucci, Perla, Ihrmark Lundberg, Kristina, Ayyalusamy, Ritish, Baig, Mohammad Hassan, Mendez, Akram, Burgos-Panadero, Rebeca, Höppner, Stefanie, Bartenhagen, Christoph, Sjövall, Daniel, Rehan, Aqsa Ali, Dattatraya Nale, Sagar, Djos, Anna, Martinsson, Tommy, Jaako, Pekka, Dong, Jae-June, Kogner, Per, Johnsen, John Inge, Fischer, Matthias, Turner, Suzanne D, Mondal, Tanmoy
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container_end_page 6335
container_issue 24
container_start_page 6310
container_title The EMBO journal
container_volume 43
creator Thombare, Ketan
Vaid, Roshan
Pucci, Perla
Ihrmark Lundberg, Kristina
Ayyalusamy, Ritish
Baig, Mohammad Hassan
Mendez, Akram
Burgos-Panadero, Rebeca
Höppner, Stefanie
Bartenhagen, Christoph
Sjövall, Daniel
Rehan, Aqsa Ali
Dattatraya Nale, Sagar
Djos, Anna
Martinsson, Tommy
Jaako, Pekka
Dong, Jae-June
Kogner, Per
Johnsen, John Inge
Fischer, Matthias
Turner, Suzanne D
Mondal, Tanmoy
description 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. Synopsis Neuroblastoma (NB) childhood cancers, associated with amplification of the MYCN oncogene, present an undifferentiated phenotype and are challenging to treat. This study reports MYCN cooperation with the m 6 A methyltransferase METTL3 promoting epitranscriptome changes and a developmental, aggressive state in early trunk neural crest cells (tNCC). m 6 A deposition regulates HOX gene expression in tNCC, ensuring their proper differentiation into sympathetic neurons. Increased MYCN levels promote METTL3 recruitment and m 6 A deposition at specific genes in tNCC, including HOX genes, which maintain an undifferentiated state in NB. Depleting or inhibiting METTL3 in MYCN-driven NB promotes cell differentiation and triggers DNA damage. Inhibiting METTL3 increases NB sensitivity to chemotherapy in mice. MYCN oncogene drives METTL3 recruitment and m 6 A deposition at posterior HOX genes, creating an undifferentiated state in early neural crest cells.
doi_str_mv 10.1038/s44318-024-00299-8
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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. Synopsis Neuroblastoma (NB) childhood cancers, associated with amplification of the MYCN oncogene, present an undifferentiated phenotype and are challenging to treat. This study reports MYCN cooperation with the m 6 A methyltransferase METTL3 promoting epitranscriptome changes and a developmental, aggressive state in early trunk neural crest cells (tNCC). m 6 A deposition regulates HOX gene expression in tNCC, ensuring their proper differentiation into sympathetic neurons. Increased MYCN levels promote METTL3 recruitment and m 6 A deposition at specific genes in tNCC, including HOX genes, which maintain an undifferentiated state in NB. Depleting or inhibiting METTL3 in MYCN-driven NB promotes cell differentiation and triggers DNA damage. Inhibiting METTL3 increases NB sensitivity to chemotherapy in mice. MYCN oncogene drives METTL3 recruitment and m 6 A deposition at posterior HOX genes, creating an undifferentiated state in early neural crest cells.</description><identifier>ISSN: 1460-2075</identifier><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.1038/s44318-024-00299-8</identifier><identifier>PMID: 39528654</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adenosine - analogs &amp; derivatives ; Adenosine - metabolism ; Animals ; Biochemistry and Molecular Biology ; Biokemi och molekylärbiologi ; Biomedical and Life Sciences ; Cell Differentiation ; Cell Line, Tumor ; EMBO03 ; EMBO09 ; EMBO27 ; Gene Expression Regulation, Neoplastic ; HOX Genes ; Humans ; Life Sciences ; Methyltransferases - genetics ; Methyltransferases - metabolism ; METTL3 ; Mice ; MYCN ; N-Myc Proto-Oncogene Protein - genetics ; N-Myc Proto-Oncogene Protein - metabolism ; Neural Crest - metabolism ; Neuroblastoma ; Neuroblastoma - genetics ; Neuroblastoma - metabolism ; Neuroblastoma - pathology</subject><ispartof>The EMBO journal, 2024-11, Vol.43 (24), p.6310-6335</ispartof><rights>The Author(s) 2024</rights><rights>2024. 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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. Synopsis Neuroblastoma (NB) childhood cancers, associated with amplification of the MYCN oncogene, present an undifferentiated phenotype and are challenging to treat. This study reports MYCN cooperation with the m 6 A methyltransferase METTL3 promoting epitranscriptome changes and a developmental, aggressive state in early trunk neural crest cells (tNCC). m 6 A deposition regulates HOX gene expression in tNCC, ensuring their proper differentiation into sympathetic neurons. Increased MYCN levels promote METTL3 recruitment and m 6 A deposition at specific genes in tNCC, including HOX genes, which maintain an undifferentiated state in NB. Depleting or inhibiting METTL3 in MYCN-driven NB promotes cell differentiation and triggers DNA damage. Inhibiting METTL3 increases NB sensitivity to chemotherapy in mice. MYCN oncogene drives METTL3 recruitment and m 6 A deposition at posterior HOX genes, creating an undifferentiated state in early neural crest cells.</description><subject>Adenosine - analogs &amp; derivatives</subject><subject>Adenosine - metabolism</subject><subject>Animals</subject><subject>Biochemistry and Molecular Biology</subject><subject>Biokemi och molekylärbiologi</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Differentiation</subject><subject>Cell Line, Tumor</subject><subject>EMBO03</subject><subject>EMBO09</subject><subject>EMBO27</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HOX Genes</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Methyltransferases - genetics</subject><subject>Methyltransferases - metabolism</subject><subject>METTL3</subject><subject>Mice</subject><subject>MYCN</subject><subject>N-Myc Proto-Oncogene Protein - genetics</subject><subject>N-Myc Proto-Oncogene Protein - metabolism</subject><subject>Neural Crest - metabolism</subject><subject>Neuroblastoma</subject><subject>Neuroblastoma - genetics</subject><subject>Neuroblastoma - metabolism</subject><subject>Neuroblastoma - pathology</subject><issn>1460-2075</issn><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kk1v1DAQhi0EomXhD3BAOXJJa8cfsU8IrQpF2sJlOXCyHHuydcnawU4W9d_jNkvVXnryfDzz2p4ZhN4TfEYwleeZMUpkjRtWY9woVcsX6JQwgesGt_zlI_sEvcn5BmPMZUteoxOqeCMFZ6coX11stxt6fvVr_b2yMY6QzORjqFzyB8hVgDmZobIJ8lQ53_eQIEx-YUxw1ZjiwbtCTteldIR58rY6zEMoXucHP91WPtzLxG4weYp78xa96s2Q4d3xXKGfXy6268t68-Prt_XnTW2pwFMtWdfJxlIGQqmWQK8cZ4rjXsi--EwwJw1vrOQOTNtCKx3pScdoJ4FZo-gK1Ytu_gvj3Okx-b1Jtzoar4-h38UCLRURij7L7-ZRl9BuvuMpo6xMYIU-LXyB9-BsaUzp1ZOyp5ngr_UuHjQhgqlWiqLw8aiQ4p-5tFjvfbYwDCZAnLOmpJEtV5zxgjYLalPMOUH_cA_B-m4d9LIOuqyDvl8HLUvRh8cvfCj5P_8C0OOXSyrsIOmbOKdQpvKc7D_DOsUT</recordid><startdate>20241111</startdate><enddate>20241111</enddate><creator>Thombare, Ketan</creator><creator>Vaid, Roshan</creator><creator>Pucci, Perla</creator><creator>Ihrmark Lundberg, Kristina</creator><creator>Ayyalusamy, Ritish</creator><creator>Baig, Mohammad Hassan</creator><creator>Mendez, Akram</creator><creator>Burgos-Panadero, Rebeca</creator><creator>Höppner, Stefanie</creator><creator>Bartenhagen, Christoph</creator><creator>Sjövall, Daniel</creator><creator>Rehan, Aqsa Ali</creator><creator>Dattatraya Nale, Sagar</creator><creator>Djos, Anna</creator><creator>Martinsson, Tommy</creator><creator>Jaako, Pekka</creator><creator>Dong, Jae-June</creator><creator>Kogner, Per</creator><creator>Johnsen, John Inge</creator><creator>Fischer, Matthias</creator><creator>Turner, Suzanne D</creator><creator>Mondal, Tanmoy</creator><general>Nature Publishing Group UK</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>F1U</scope><orcidid>https://orcid.org/0009-0003-7099-0644</orcidid><orcidid>https://orcid.org/0000-0003-1277-812X</orcidid><orcidid>https://orcid.org/0000-0001-6228-8001</orcidid><orcidid>https://orcid.org/0000-0003-1264-3487</orcidid><orcidid>https://orcid.org/0000-0002-0183-3376</orcidid><orcidid>https://orcid.org/0000-0001-8227-4838</orcidid><orcidid>https://orcid.org/0000-0003-0811-2675</orcidid><orcidid>https://orcid.org/0009-0003-8081-9357</orcidid><orcidid>https://orcid.org/0000-0003-1363-1242</orcidid><orcidid>https://orcid.org/0000-0002-2074-5080</orcidid><orcidid>https://orcid.org/0000-0003-3587-8318</orcidid><orcidid>https://orcid.org/0009-0008-9030-7992</orcidid></search><sort><creationdate>20241111</creationdate><title>METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma</title><author>Thombare, Ketan ; 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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. Synopsis Neuroblastoma (NB) childhood cancers, associated with amplification of the MYCN oncogene, present an undifferentiated phenotype and are challenging to treat. This study reports MYCN cooperation with the m 6 A methyltransferase METTL3 promoting epitranscriptome changes and a developmental, aggressive state in early trunk neural crest cells (tNCC). m 6 A deposition regulates HOX gene expression in tNCC, ensuring their proper differentiation into sympathetic neurons. Increased MYCN levels promote METTL3 recruitment and m 6 A deposition at specific genes in tNCC, including HOX genes, which maintain an undifferentiated state in NB. Depleting or inhibiting METTL3 in MYCN-driven NB promotes cell differentiation and triggers DNA damage. Inhibiting METTL3 increases NB sensitivity to chemotherapy in mice. MYCN oncogene drives METTL3 recruitment and m 6 A deposition at posterior HOX genes, creating an undifferentiated state in early neural crest cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>39528654</pmid><doi>10.1038/s44318-024-00299-8</doi><tpages>26</tpages><orcidid>https://orcid.org/0009-0003-7099-0644</orcidid><orcidid>https://orcid.org/0000-0003-1277-812X</orcidid><orcidid>https://orcid.org/0000-0001-6228-8001</orcidid><orcidid>https://orcid.org/0000-0003-1264-3487</orcidid><orcidid>https://orcid.org/0000-0002-0183-3376</orcidid><orcidid>https://orcid.org/0000-0001-8227-4838</orcidid><orcidid>https://orcid.org/0000-0003-0811-2675</orcidid><orcidid>https://orcid.org/0009-0003-8081-9357</orcidid><orcidid>https://orcid.org/0000-0003-1363-1242</orcidid><orcidid>https://orcid.org/0000-0002-2074-5080</orcidid><orcidid>https://orcid.org/0000-0003-3587-8318</orcidid><orcidid>https://orcid.org/0009-0008-9030-7992</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1460-2075
ispartof The EMBO journal, 2024-11, Vol.43 (24), p.6310-6335
issn 1460-2075
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1460-2075
language eng
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subjects Adenosine - analogs & derivatives
Adenosine - metabolism
Animals
Biochemistry and Molecular Biology
Biokemi och molekylärbiologi
Biomedical and Life Sciences
Cell Differentiation
Cell Line, Tumor
EMBO03
EMBO09
EMBO27
Gene Expression Regulation, Neoplastic
HOX Genes
Humans
Life Sciences
Methyltransferases - genetics
Methyltransferases - metabolism
METTL3
Mice
MYCN
N-Myc Proto-Oncogene Protein - genetics
N-Myc Proto-Oncogene Protein - metabolism
Neural Crest - metabolism
Neuroblastoma
Neuroblastoma - genetics
Neuroblastoma - metabolism
Neuroblastoma - pathology
title METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma
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