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Although the highly conserved glycoprotein slit guidance ligand 2 (SLIT2), implicated in axon guidance, has been proposed to support normal haematopoietic stem cell (HSC) function, its role in AML pathogenesis remains poorly defined. Here, we show that\n                    <jats:italic>SLIT2<\/jats:italic>\n                    is downregulated in mesenchymal stem cells (MSCs) from AML patients. Patients with higher\u2010than\u2010normal SLIT2 protein levels had better outcomes, independently of classical risk factors. Functionally, knocking down (KD)\n                    <jats:italic>SLIT2<\/jats:italic>\n                    in MSCs caused a reprogramming of the microenvironment. Specifically,\n                    <jats:italic>SLIT2<\/jats:italic>\n                    \u2010KD in MSCs resulted in increased expression of LSC\u2010supporting genes including C\u2010X\u2010C motif chemokne ligand 12 (\n                    <jats:italic>CXCL12)<\/jats:italic>\n                    and KIT proto\u2010oncogene, receptor tyrosine kinase (\n                    <jats:italic>KIT<\/jats:italic>\n                    ), and co\u2010culture of primary AML cells on\n                    <jats:italic>SLIT2<\/jats:italic>\n                    \u2010KD stromal cells prevented myeloid differentiation. Conversely, the addition of recombinant SLIT2 had cytostatic effects on AML cells, resulting in reduced proliferation and reduced clonogenicity in all tested models. Furthermore, in human xenograft models, systemic administration of recombinant SLIT2 resulted in a decrease in leukaemic burden in BM and spleen, delayed disease progression and improved survival. Overall, these data demonstrate that SLIT2 may act as a tumour suppressor, while\n                    <jats:italic>SLIT2<\/jats:italic>\n                    loss impairs myeloid terminal differentiation, suggesting that SLIT2 signalling could serve as a potential therapeutic axis in AML.\n                  <\/jats:p>","DOI":"10.1111\/bjh.70785","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:31:38Z","timestamp":1790310698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SLIT2 modulates leukaemic cell proliferation and stromal support in acute myeloid leukaemia models"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0827-5848","authenticated-orcid":false,"given":"Luise","family":"Albuquerque\u2010Sim\u00f5es","sequence":"first","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"},{"name":"Center for Cell\u2010Based Therapy University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"},{"name":"Hematology Division, LIM31, Faculty of Medicine University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"},{"name":"Department of Hematology Institute of Cancer of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Weinh\u00e4user","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"},{"name":"Myeloid Leukaemia Genomics and Biology Group, School of Cancer and Pharmaceutical Sciences King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-4311","authenticated-orcid":false,"given":"Diego A.","family":"Pereira\u2010Martins","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"},{"name":"Myeloid Leukaemia Genomics and Biology Group, School of Cancer and Pharmaceutical Sciences King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar Alexander Ortiz","family":"Rojas","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"},{"name":"Department of Hematology Institute of Cancer of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3417-5557","authenticated-orcid":false,"given":"L\u00facio Henrique Sousa","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"},{"name":"Center for Cell\u2010Based Therapy University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"},{"name":"Hematology Division, LIM31, Faculty of Medicine University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"},{"name":"Department of Hematology Institute of Cancer of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6635-0247","authenticated-orcid":false,"given":"Livia Bassani Lins","family":"de Miranda","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago Mantello","family":"Bianco","sequence":"additional","affiliation":[{"name":"Center for Cell\u2010Based Therapy University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4643-4141","authenticated-orcid":false,"given":"Rita de C\u00e1ssia","family":"Cavaglieri","sequence":"additional","affiliation":[{"name":"Hematology Division, LIM31, Faculty of Medicine University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariane Cristina","family":"do Nascimento","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Centre Groningen University of Groningen  Groningen The Netherlands"},{"name":"Hematology Division, LIM31, Faculty of Medicine University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"},{"name":"Department of Hematology Institute of Cancer of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0221-5761","authenticated-orcid":false,"given":"Lynn","family":"Quek","sequence":"additional","affiliation":[{"name":"Myeloid Leukaemia Genomics and Biology Group, School of Cancer and Pharmaceutical Sciences King's College London  London 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