Infection exposure is a causal factor in B-cell precursor acute lymphoblastic leukemia as a result of Pax5-inherited susceptibility

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 specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development. [Significance]: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease.J. Hauer has been supported by the German Children’s Cancer Foundation and from the “Forschungskommission” of the medical faculty of the Heinrich Heine University and the “Strategischer Forschungsfond” of the Heinrich Heine University. S. Ginzel has been supported by a scholarship from the Hochschule Bonn-Rhein-Sieg. A. Borkhardt has been supported by the German Children’s Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Funding to S.N. Constantinescu from Salus Sanguinis, Fondation contre le cancer Belgium; Interuniversity Attraction Poles IAP, and ARC 10/15-027 is acknowledged. Research in the I. Sánchez-García group is partially supported by FEDER and MINECO (SAF2012-32810 and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), Junta de Castilla y León (BIO/SA32/14 , BIO/SA51/15, and CSI001U14), Fundacion Inocente Inocente, and the ARIMMORA project [European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement no. 282891]. The I. Sánchez-García lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A. Borkhardt and I. SánchezGarcía have been supported by the German Carreras Foundation (DJCLS R13/26). Research in the C. Vicente-Dueñas group is partially supported by a “Miguel Servet” Grant (CP14/00082 - AES 2013-2016) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad). Research at C. Cobaleda’s lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI13/00160 and PI14/00025), and from an institutional grant from the Fundacion Ramon Areces. A. MartínLorenzo was supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13).Peer Reviewe