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Isidro-Hernández, Marta; Mayado, Andrea; Casado-García, Ana; Martínez-Cano, Jorge; Palmi, Chiara; Fazio, Grazia; Orfao, Alberto; Ribera, Jordi; Ribera, Josep Maria; Zamora, Lurdes; Raboso-Gallego, Javier; Blanco, Oscar; Alonso-López, Diego; De Las Rivas, Javier; Jiménez, Rafael; García Criado, Francisco Javier; García Cenador, María Begoña; Ramírez-Orellana, Manuel; Cazzaniga, Giovanni; Cobaleda, César; Vicente-Dueñas, Carolina; Sánchez-García, Isidro

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

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  • Media type: E-Article
  • Title: Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis
  • Contributor: Isidro-Hernández, Marta; Mayado, Andrea; Casado-García, Ana; Martínez-Cano, Jorge; Palmi, Chiara; Fazio, Grazia; Orfao, Alberto; Ribera, Jordi; Ribera, Josep Maria; Zamora, Lurdes; Raboso-Gallego, Javier; Blanco, Oscar; Alonso-López, Diego; De Las Rivas, Javier; Jiménez, Rafael; García Criado, Francisco Javier; García Cenador, María Begoña; Ramírez-Orellana, Manuel; Cazzaniga, Giovanni; Cobaleda, César; Vicente-Dueñas, Carolina; Sánchez-García, Isidro
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Scientific Reports
  • Language: English
  • DOI: 10.1038/s41598-020-76206-y
  • ISSN: 2045-2322
  • Keywords: Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p><jats:italic>PAX5</jats:italic> is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic <jats:italic>PAX5</jats:italic> mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that <jats:italic>Pax5</jats:italic> heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of <jats:italic>IL-6</jats:italic> in these <jats:italic>Pax5</jats:italic> heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in <jats:italic>Pax5</jats:italic> mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL–6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by <jats:italic>Pax5</jats:italic> loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by <jats:italic>PAX5</jats:italic> loss.</jats:p>
  • Access State: Open Access