Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID
Summary
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.
| Authors | Rodríguez-Hernández G, Opitz FV, Delgado P, Walter C, Álvarez-Prado ÁF, González-Herrero I, Auer F, Fischer U, Janssen S, Bartenhagen C, Raboso-Gallego J, Casado-García A, Orfao A, Blanco O, Alonso-López D, Rivas JL, Tena-Dávila SG, Müschen M, Dugas M, Criado FJG, Cenador MBG, Vicente-Dueñas C, Hauer J, Ramiro AR, Sanchez-Garcia I, Borkhardt A |
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| Journal | Nature communications |
| Publication Date | 2019 Dec 5;10(1):5563 |
| PubMed | 31804490 |
| PubMed Central | PMC6895129 |
| DOI | 10.1038/s41467-019-13570-y |