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NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLL-r B-ALL by regulating NR3C1 expression.
Lopez-Millan, Belén; Rubio-Gayarre, Alba; Vinyoles, Meritxell; Trincado, Juan L; Fraga, Mario F; Fernandez-Fuentes, Narcís; Guerrero-Murillo, Mercedes; Martinez-Moreno, Alba; Velasco-Hernandez, Talia; Falgàs, Aïda; Panisello, Carla; Valcarcel, Gemma; Sardina, Jose Luis; López-Martí, Paula; Javierre, Biola M; Del Valle-Pérez, Beatriz; García de Herreros, Antonio; Locatelli, Franco; Pieters, Rob; Bardini, Michela; Cazzaniga, Giovanni; Rodríguez-Manzaneque, Juan Carlos; Hanewald, Thomas; Marschalek, Rolf; Milne, Thomas A; Stam, Ronald W; Tejedor, Juan Ramón Ramón; Menendez, Pablo; Bueno, Clara.
Afiliación
  • Lopez-Millan B; Josep Carreras Leukemia Research Institute, Barcelona, Spain.
  • Rubio-Gayarre A; Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
  • Vinyoles M; Josep Carreras Leukemia Research Institute, Barcelona, Spain.
  • Trincado JL; Josep Carreras Leukemia Research Institute, Barcelona, Spain.
  • Fraga MF; CINN-ISPA, Oviedo, Spain.
  • Fernandez-Fuentes N; Josep Carreras Leukemia Research Institute., Barcelona, Spain.
  • Guerrero-Murillo M; Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
  • Martinez-Moreno A; Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine,, Barcelona, Spain.
  • Velasco-Hernandez T; Josep Carreras Leukemia Research Institute., Barcelona, Spain.
  • Falgàs A; Josep Carreras Leukemia Research Institute, Barcelona, Spain.
  • Panisello C; Josep Carreras Leukemia Research Institute, Barcelona, Spain.
  • Valcarcel G; Josep Carreras Leukemia Research Institute, Badalona, Spain.
  • Sardina JL; Josep Carreras Leukaemia Research Institute, Badalona, Spain.
  • López-Martí P; Josep Carreras Leukaemia Research Institute, Badalona, Spain.
  • Javierre BM; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain.
  • Del Valle-Pérez B; Programa de Recerca en Cancer. Hospital del Mar Research Institute (IMIM) and Department of Medicine and Life Science. Universitat Pompeu Fabra, Barcelona, Spain.
  • García de Herreros A; Hospital del Mar Research Institute, Barcelona, Spain.
  • Locatelli F; Bambino Gesù Children's Hospital, Catholic University of Sacred Heart, Rome, Italy.
  • Pieters R; Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • Bardini M; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
  • Cazzaniga G; Fondazione Tettamanti, Monza, Italy.
  • Rodríguez-Manzaneque JC; GENYO. Center for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain.
  • Hanewald T; Goethe-University of Frankfurt/Main, Frankfurt, Germany.
  • Marschalek R; Goethe-University of Frankfurt/Main, Frankfurt, Germany.
  • Milne TA; University of Oxford, Oxford, United Kingdom.
  • Stam RW; Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • Tejedor JRR; Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Oviedo, Spain.
  • Menendez P; Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
  • Bueno C; Josep Carreras Leukemia Research Institute, Barcelona, Spain.
Blood ; 2024 Aug 02.
Article en En | MEDLINE | ID: mdl-39093982
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 (<30%), frequent 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 and that anti-NG2 immunotherapy strongly reduces/delays relapse in MLLr B-ALL xenograft models. Despite its contribution to MLLr B-ALL pathogenesis and its diagnostic utility, 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-AF4 fusion protein. NG2 negatively regulates the expression of the GC receptor NR3C1 and confers GC resistance to MLLr B-ALL cells in vitro and in vivo. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via AP-1-mediated trans-repression. 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos