1. Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID
- Author
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Rodriguez-Hernandez, Guillermo, Opitz, Friederike V., Delgado, Pilar, Walter, Carolin, Alvarez-Prado, Angel F., Gonzalez-Herrero, Ines, Auer, Franziska, Fischer, Ute, Janssen, Stefan, Bartenhagen, Christoph, Raboso-Gallego, Javier, Casado-Garcia, Ana, Orfao, Alberto, Blanco, Oscar, Alonso-Lopez, Diego, De Las Rivas, Javier, Gonzalez de Tena-Davila, Sara, Muschen, Markus, Dugas, Martin, Garcia Criado, Francisco Javier, Garcia Cenador, Maria Begona, Vicente-Duenas, Carolina, Hauer, Julia, Ramiro, Almudena R., Sanchez-Garcia, Isidro, Borkhardt, Arndt, Rodriguez-Hernandez, Guillermo, Opitz, Friederike V., Delgado, Pilar, Walter, Carolin, Alvarez-Prado, Angel F., Gonzalez-Herrero, Ines, Auer, Franziska, Fischer, Ute, Janssen, Stefan, Bartenhagen, Christoph, Raboso-Gallego, Javier, Casado-Garcia, Ana, Orfao, Alberto, Blanco, Oscar, Alonso-Lopez, Diego, De Las Rivas, Javier, Gonzalez de Tena-Davila, Sara, Muschen, Markus, Dugas, Martin, Garcia Criado, Francisco Javier, Garcia Cenador, Maria Begona, Vicente-Duenas, Carolina, Hauer, Julia, Ramiro, Almudena R., Sanchez-Garcia, Isidro, and Borkhardt, Arndt
- 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.
- Published
- 2019