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| Pàgina inicial > Articles > Articles publicats > Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis |
(Centro de Investigación Biomédica en Red de Cáncer) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universidad de Salamanca. Departamento de Fisiología y Farmacología) (Hospital Infantil Universitario Niño Jesús (Madrid)) (Centro Ricerca Tettamanti. Dept of Medicine. University of Milan Bicocca) (Centro de Biología Molecular Severo Ochoa)| Data: | 2020 |
| Resum: | PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 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 Pax5 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 IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 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 Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss. |
| Ajuts: | Ministerio de Economía y Competitividad SAF2017-83061-R Instituto de Salud Carlos III CPII19-00024-AES2017-2020 Instituto de Salud Carlos III PI17-00167 Ministerio de Economía y Competitividad SAF2015-64420-R Ministerio de Ciencia e Innovación RTI2018-093314-B-I00 Instituto de Salud Carlos III PI19-01183 |
| Nota: | Altres ajuts: We would like to thank the "Fundación Ramón Areces," a Research Contract with the "Fundación Síndrome de Wolf-Hirschhorn o 4p-", and institutional grants from the "Fundación Ramón Areces" and "Banco de Santander" to the CBMSO. Research in the ISG group is partially supported by by Junta de Castilla y León (UIC-017, CSI001U16, and CSI234P18), and by the German Jose Carreras Foundation (DJCLS R13/26; DJCLS 07R/2019). AC-G and M.I.-H. are supported by FSE-Conserjería de Educación de la Junta de Castilla y León 2019 and 2020 (ESF- European Social Fund) fellowship, respectively. J.R.-G. is supported by a scholarship from University of Salamanca co-financed by Banco Santander and ESF. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Cancer ; Cancer genetics ; Cancer models ; Cancer therapy |
| Publicat a: | Scientific reports, Vol. 10 Núm. 1 (january 2020) , p. 19189, ISSN 2045-2322 |
