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Cancer Discov. 2015 Dec;5(12):1328-43. doi: 10.1158/2159-8290.CD-15-0892. Epub 2015 Sep 25.

Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility.

Author information

1
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
2
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany.
3
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany. Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
4
Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
5
Ludwig Institute for Cancer Research Brussels and Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
6
Institute of Medical Informatics, University of Muenster, Muenster, Germany.
7
Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
8
Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
9
Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
10
Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain. Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
11
Centro de Biología Molecular Severo Ochoa; CSIC/Universidad Autónoma de Madrid; Campus de Cantoblanco, Madrid, Spain.
12
Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
13
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Arndt.Borkhardt@med.uni-duesseldorf.de isg@usal.es.
14
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany. Arndt.Borkhardt@med.uni-duesseldorf.de isg@usal.es.

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 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.

Comment in

PMID:
26408659
DOI:
10.1158/2159-8290.CD-15-0892
[Indexed for MEDLINE]
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