NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression

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• dc.contributor.author López Millán, Belén
• dc.contributor.author Valle Pérez, Beatriz del
• dc.contributor.author García de Herreros, Antonio
• dc.contributor.author Bueno, Clara
• dc.date.accessioned 2025-03-07T07:05:08Z
• dc.date.embargoEnd info:eu-repo/date/embargoEnd/2025-11-07
• dc.date.issued 2024
• dc.description.abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ∼85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival, relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL, and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis in MLLr B-ALL. Despite its contribution to MLLr B-ALL pathogenesis, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here, we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-ALF transcription elongation factor 4 (AF4) fusion protein. NG2 negatively regulates the expression of the GC receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) and confers GC resistance to MLLr B-ALL cells. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via activating protein-1 (AP-1)-mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.
• dc.description.sponsorship The authors thank CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for core support, and the Cure2MLL project from the Fight Kids Cancer program of the European Science Foundation. Further financial support for this work was obtained from the Spanish Ministry of Economy and Competitiveness (PID2019-108160RB-I00 to P.M.), “Heroes hasta la médula” initiative and ISCIII-RICORS-TERAV within the Next Generation EU program (plan de recuperación, transformación y resiliencia), and the Health Institute Carlos III (ISCIII/FEDER, PI20/00822), the Asociación Española Contra el Cáncer, and the Fundación Unoentrecienmil to C.B. B.L.-M. was supported by the Asociación Española Contra el Cáncer (INVES20011LÓPE), Consejería de Salud y Familia (FEDER/PEER-0028-2020), and EMERGIA2021, funded by Consejería de Universidad, Investigación e Innovación, and by ERDF A way of making Europe. C.P. was supported by the Health Institute Carlos III (ISCIII/FEDER, FI21/00161). R.M. is supported by a grant from the DJCLS (07 R/2022).
• dc.embargo.liftdate 2025-11-07
• dc.format.mimetype application/pdf
• dc.identifier.citation Lopez-Millan B, Rubio-Gayarre A, Vinyoles M, Trincado JL, Fraga MF, Fernandez-Fuentes N, et al. NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression. Blood. 2024 Nov 7;144(19):2002-17. DOI: 10.1182/blood.2023022050
• dc.identifier.doi http://dx.doi.org/10.1182/blood.2023022050
• dc.identifier.issn 0006-4971
• dc.identifier.uri http://hdl.handle.net/10230/69844
• dc.language.iso eng
• dc.publisher American Society of Hematology (ASH Publications)
• dc.relation.ispartof Blood. 2024 Nov 7;144(19):2002-17
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108160RB-I00
• dc.rights © 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
• dc.rights.accessRights info:eu-repo/semantics/embargoedAccess
• dc.subject.other Leucèmia limfoblàstica
• dc.subject.other Glucocorticoides
• dc.title NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion