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

Guillermo Rodríguez-Hernández, Friederike V. Opitz, Pilar Delgado, Carolin Walter, Ángel F. Álvarez-Prado, Inés González-Herrero, Franziska Auer, Ute Fischer, Stefan Janssen, Christoph Bartenhagen, Javier Raboso-Gallego, Ana Casado-García, Alberto Orfao, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Sara González de Tena-Dávila, Markus Müschen, Martin Dugas, Francisco Javier García Criado, María Begoña García Cenador, Carolina Vicente-Dueñas, Julia Hauer (), Almudena R. Ramiro, Isidro Sanchez-Garcia () and Arndt Borkhardt ()
Additional contact information
Guillermo Rodríguez-Hernández: CSIC/Universidad de Salamanca
Friederike V. Opitz: Heinrich Heine University
Pilar Delgado: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares
Carolin Walter: University of Muenster
Ángel F. Álvarez-Prado: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares
Inés González-Herrero: CSIC/Universidad de Salamanca
Franziska Auer: Heinrich Heine University
Ute Fischer: Heinrich Heine University
Stefan Janssen: Heinrich Heine University
Christoph Bartenhagen: University Children’s Hospital of Cologne, Medical Faculty
Javier Raboso-Gallego: CSIC/Universidad de Salamanca
Ana Casado-García: CSIC/Universidad de Salamanca
Alberto Orfao: Institute of Biomedical Research of Salamanca (IBSAL)
Oscar Blanco: Institute of Biomedical Research of Salamanca (IBSAL)
Diego Alonso-López: Bioinformatics Unit, Cancer Research Center (CSIC-USAL)
Javier De Las Rivas: Institute of Biomedical Research of Salamanca (IBSAL)
Sara González de Tena-Dávila: CSIC/Universidad de Salamanca
Markus Müschen: City of Hope Comprehensive Cancer Center
Martin Dugas: University of Muenster
Francisco Javier García Criado: Institute of Biomedical Research of Salamanca (IBSAL)
María Begoña García Cenador: Institute of Biomedical Research of Salamanca (IBSAL)
Carolina Vicente-Dueñas: Institute of Biomedical Research of Salamanca (IBSAL)
Julia Hauer: Heinrich Heine University
Almudena R. Ramiro: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares
Isidro Sanchez-Garcia: CSIC/Universidad de Salamanca
Arndt Borkhardt: Heinrich Heine University

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13570-y

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