{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T19:48:07Z","timestamp":1771703287963,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kom Op Tegen Kanker"},{"name":"vzw Kinderkankerfonds"},{"name":"METOYOU foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite advances in outcome, one third of children with acute myeloid leukemia (AML) relapse, and less than half will achieve long-term survival. Relapse in AML has been shown to be driven in part by leukemic stem cells (LSCs), highlighting the unmet medical need to better characterize and target this therapy-resistant cell population. Micro-array profiling of pediatric AML subpopulations (LSCs and leukemic myeloblasts) and their healthy counterparts revealed nidogen-1 (NID1) as expressed in both leukemic subpopulations while absent in the hematopoietic stem cell. Using the TARGET dataset including pediatric AML patients (n = 1025), NID1 expression showed a correlation with worse event-free survival and KMT2A rearrangements. Drug response profiling of a NID1 knockdown model demonstrated differential sensitivity to HSP90 inhibition. RNA sequencing and gene set enrichment analysis between NID1high and NID1low phenotypes showed involvement of NID1 in mitochondrial metabolic pathways known to be enriched in LSCs. Altogether, this study highlights NID1 as a novel oncogene associated with worse EFS and metabolic LSC phenotype in AML. NID1 could serve as a biomarker and aid in further mapping LSCs to establish therapeutic strategies tackling the high relapse rates in pediatric AML.<\/jats:p>","DOI":"10.3390\/ijms26073011","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T04:17:14Z","timestamp":1742962634000},"page":"3011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Nidogen-1, a Player in KMT2A-Rearranged Pediatric Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2604-0727","authenticated-orcid":false,"given":"Jolien","family":"Vanhooren","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larissa","family":"Deneweth","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5500-3522","authenticated-orcid":false,"given":"Luca","family":"Pagliaro","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43121 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, 43121 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7598-9584","authenticated-orcid":false,"given":"Zhiyao","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8748-7012","authenticated-orcid":false,"given":"Mariateresa","family":"Giaimo","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43121 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, 43121 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3313-1387","authenticated-orcid":false,"given":"Rafaella","family":"Zamponi","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43121 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, 43121 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Roti","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43121 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, 43121 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Depreter","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, AZ Delta General Hospital, 8800 Roeselare, Belgium"},{"name":"Department of Haematology, Vrije Universiteit Brussel (VUB), 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattias","family":"Hofmans","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"De Moerloose","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hematology-Oncology and 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A. (2019). Response-Guided Chemotherapy for Pediatric Acute Myeloid Leukemia without Hematopoietic Stem Cell Transplantation in First Complete Remission: Results from Protocol DB AML-01. Pediatr. Blood Cancer, 66.","DOI":"10.1002\/pbc.27605"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rasche, M., Zimmermann, M., Steidel, E., Alonzo, T., Aplenc, R., Bourquin, J.-P., Boztug, H., Cooper, T., Gamis, A.S., and Gerbing, R.B. (2021). Survival Following Relapse in Children with Acute Myeloid Leukemia: A Report from AML-BFM and COG. Cancers, 13.","DOI":"10.3390\/cancers13102336"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1182\/bloodadvances.2020003709","article-title":"Genomic Characterization of Relapsed Acute Myeloid Leukemia Reveals Novel Putative Therapeutic Targets","volume":"5","author":"Stratmann","year":"2021","journal-title":"Blood Adv."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Marchand, T., and Pinho, S. (2021). Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.775128"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"344","DOI":"10.20517\/cdr.2021.140","article-title":"Characteristics of Leukemic Stem Cells in Acute Leukemia and Potential Targeted Therapies for Their Specific Eradication","volume":"5","author":"Hansen","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.3324\/haematol.2019.222612","article-title":"TARP Is an Immunotherapeutic Target in Acute Myeloid Leukemia Expressed in the Leukemic Stem Cell Compartment","volume":"105","author":"Depreter","year":"2020","journal-title":"Haematologica"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3396","DOI":"10.1073\/pnas.0900089106","article-title":"Dysregulated Gene Expression Networks in Human Acute Myelogenous Leukemia Stem Cells","volume":"106","author":"Majeti","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.matbio.2013.07.009","article-title":"Structural Elucidation of Full-Length Nidogen and the Laminin\u2013Nidogen Complex in Solution","volume":"33","author":"Patel","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.gendis.2021.03.004","article-title":"Nidogen: A Matrix Protein with Potential Roles in Musculoskeletal Tissue Regeneration","volume":"9","author":"Zhou","year":"2021","journal-title":"Genes Dis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rokavec, M., Jaeckel, S., and Hermeking, H. (2023). Nidogen-1\/NID1 Function and Regulation during Progression and Metastasis of Colorectal Cancer. Cancers, 15.","DOI":"10.3390\/cancers15225316"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33110","DOI":"10.18632\/oncotarget.16145","article-title":"NID1, a New Regulator of EMT Required for Metastasis and Chemoresistance of Ovarian Cancer Cells","volume":"8","author":"Zhou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mao, X., Tey, S.K., Yeung, C.L.S., Kwong, E.M.L., Fung, Y.M.E., Chung, C.Y.S., Mak, L.-Y., Wong, D.K.H., Yuen, M.-F., and Ho, J.C.M. (2020). Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1. Adv. Sci., 7.","DOI":"10.1002\/advs.202002157"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Murphy, L.A., and Winters, A.C. (2023). Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells. Biomedicines, 11.","DOI":"10.20944\/preprints202311.1010.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1200\/JCO.23.01841","article-title":"Mitoxantrone Versus Liposomal Daunorubicin in Induction of Pediatric AML With Risk Stratification Based on Flow Cytometry Measurement of Residual Disease","volume":"42","author":"Tierens","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/s41375-019-0604-8","article-title":"A 6-Gene Leukemic Stem Cell Score Identifies High Risk Pediatric Acute Myeloid Leukemia","volume":"34","author":"Elsayed","year":"2020","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature20598","article-title":"A 17-Gene Stemness Score for Rapid Determination of Risk in Acute Leukaemia","volume":"540","author":"Ng","year":"2016","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11842","DOI":"10.1073\/pnas.2034201100","article-title":"Normal and Leukemic Hematopoiesis: Are Leukemias a Stem Cell Disorder or a Reacquisition of Stem Cell Characteristics?","volume":"100","author":"Jamieson","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wesely, J., Kotini, A.G., Izzo, F., Luo, H., Yuan, H., Sun, J., Georgomanoli, M., Zviran, A., Deslauriers, A.G., and Dusaj, N. (2020). Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells. Cell Rep., 31.","DOI":"10.1016\/j.celrep.2020.107688"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/s41375-023-01877-1","article-title":"The KMT2A Recombinome of Acute Leukemias in 2023","volume":"37","author":"Meyer","year":"2023","journal-title":"Leukemia"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Guarnera, L., D\u2019Addona, M., Bravo-Perez, C., and Visconte, V. (2024). KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25169023"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1182\/bloodadvances.2023011771","article-title":"Optimized Cytogenetic Risk-Group Stratification of KMT2A-Rearranged Pediatric Acute Myeloid Leukemia","volume":"8","author":"Harrison","year":"2024","journal-title":"Blood Adv."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Cabaud-Gibouin, V., Durand, M., Qu\u00e9r\u00e9, R., Girodon, F., Garrido, C., and Jego, G. (2023). Heat-Shock Proteins in Leukemia and Lymphoma: Multitargets for Innovative Therapeutic Approaches. Cancers, 15.","DOI":"10.3390\/cancers15030984"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Magliulo, D., and Bernardi, R. (2022). Hypoxic Stress and Hypoxia-Inducible Factors in Leukemias. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.973978"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Velasco-Hernandez, T., Trincado, J.L., Vinyoles, M., Closa, A., Mart\u00ednez-Moreno, A., Guti\u00e9rrez-Ag\u00fcera, F., Molina, O., Rodr\u00edguez-Cortez, V.C., Ximeno-Parpal, P., and Fern\u00e1ndez-Fuentes, N. (2024). Integrative Single-Cell Expression and Functional Studies Unravels a Sensitization to Cytarabine-Based Chemotherapy through HIF Pathway Inhibition in AML Leukemia Stem Cells. HemaSphere, 8.","DOI":"10.1002\/hem3.45"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Han, N., Li, X., Wang, Y., Li, H., Zhang, C., Zhao, X., Zhang, Z., Ruan, M., and Zhang, C. (2022). HIF-1\u03b1 Induced NID1 Expression Promotes Pulmonary Metastases via the PI3K-AKT Pathway in Salivary Gland Adenoid Cystic Carcinoma. Oral Oncol., 131.","DOI":"10.1016\/j.oraloncology.2022.105940"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Masgras, I., Sanchez-Martin, C., Colombo, G., and Rasola, A. (2017). The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells. Front. Oncol., 7.","DOI":"10.3389\/fonc.2017.00058"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.molmed.2020.10.001","article-title":"Extinguishing the Embers: Targeting AML Metabolism","volume":"27","author":"Pietras","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_28","first-page":"32","article-title":"The Dutch-Belgian Pediatric Acute Myeloid Leukemia Protocol for Chil- Dren with Newly Diagnosed Acute Myeloid Leukemia (DB AML-01)","volume":"1","author":"Moerloose","year":"2010","journal-title":"Belg. J. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ritchie, M.E., Phipson, B., Wu, D., Hu, Y., Law, C.W., Shi, W., and Smyth, G.K. (2015). Limma Powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies. Nucleic Acids Res., 43.","DOI":"10.1093\/nar\/gkv007"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.cell.2017.06.010","article-title":"Defining a Cancer Dependency Map","volume":"170","author":"Tsherniak","year":"2017","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., and Speleman, F. (2002). Accurate Normalization of Real-Time Quantitative RT-PCR Data by Geometric Averaging of Multiple Internal Control Genes. Genome Biol., 3.","DOI":"10.1186\/gb-2002-3-7-research0034"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1158\/2159-8290.CD-13-0350","article-title":"Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia","volume":"3","author":"Pemovska","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yadav, B., Pemovska, T., Szwajda, A., Kulesskiy, E., Kontro, M., Karjalainen, R., Majumder, M.M., Malani, D., Murum\u00e4gi, A., and Knowles, J. (2014). Quantitative Scoring of Differential Drug Sensitivity for Individually Optimized Anticancer Therapies. Sci. Rep., 4.","DOI":"10.1038\/srep05193"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3011\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:00:19Z","timestamp":1760029219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073011"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073011","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]}}}