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Nat Commun. 2019 Dec 5;10(1):5563. doi: 10.1038/s41467-019-13570-y.

Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID.

Author information

1
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain.
2
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
3
Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
4
B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
5
Institute of Medical Informatics, University of Muenster, Muenster, Germany.
6
Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, California, 91016, USA.
7
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.
8
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
9
Servicio de Citometría, Departamento de Medicina, CIBERON, and Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain.
10
Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
11
Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
12
Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
13
Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
14
Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany. Julia.Hauer@med.uni-duesseldorf.de.
15
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain. isg@usal.es.
16
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. isg@usal.es.
17
Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany. Arndt.Borkhardt@med.uni-duesseldorf.de.

Abstract

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies. However, whether this mechanism governs native non-transplant B-ALL development is unknown. Here we show that, surprisingly, AID genetic deletion does not affect B-ALL development in Pax5-haploinsufficient mice prone to B-ALL upon natural infection exposure. We next test the effect of premature AID expression from earliest pro-B-cell stages in B-cell transformation. The generation of AID off-target mutagenic activity in precursor B-cells does not promote B-ALL. Likewise, known drivers of human B-ALL are not preferentially targeted by AID. Overall these results suggest that infections promote B-ALL through AID-independent mechanisms, providing evidence for a new model of childhood B-ALL development.

PMID:
31804490
DOI:
10.1038/s41467-019-13570-y
Free PMC Article

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