Reference

PortadaCancerDiscoveryCancer Discov; 2015 Dec;5(12):1328-43. doi: 10.1158/2159-8290.CD-15-0892.

Authors

Alberto Martín-Lorenzo, Julia Hauer, Carolina Vicente-Dueñas, Franziska Auer, Inés González-Herrero, Idoia García-Ramírez, Sebastian Ginzel, Ralf Thiele, Stefan N. Constantinescu, Christoph Bartenhagen, Martin Dugas, Michael Gombert , Daniel Schäfer, Oscar Blanco, Andrea Mayado, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, César Cobaleda, María Begoña García-Cenador, Francisco Javier García-Criado, Isidro Sánchez-García, and Arndt Borkhardt.

Abstract

Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5+/− leukemic cells with specificJAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development.

Description

Las infecciones fueron propuestas como causa del desarrollo de pB-ALL por primera en 1917 por G. Ward. Sin embargo, hasta la fecha no existían evidencias científicas que soportaran esta hipótesis. Los resultados publicados en Cancer Discovery, demuestran por primera vez que la exposición a infección causa leucemia en ratones con una susceptibilidad genética heredada, mostrando que el desarrollo de pB-ALL se produce en ratones Pax5+/- solamente cuando son expuestos a infección.

 

Fotogrupofeb

 

REFERENCIA DEL GRUPO INVESTIGADOR

Este trabajo es el fruto de la colaboración internacional entre los grupos dirigidos por Prof. Arndt Borkhardt en Dusseldorf (Heinrich-Heine University Dusseldorf, Germany) e Isidro Sánchez-García en Salamanca (IBMCC-CIC). Esta investigación demuestra por primera vez cómo la infección causa leucemia.

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