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 CriadoMaría Begoña García Cenador, Carolina Vicente-Dueñas, Julia Hauer, Almudena R. Ramiro, Isidro Sanchez-Garcia*, Arndt Borkhardt

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Article number5563
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

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