Abstract
AbstractThe 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference70 articles.
1. Parkin, D. M., Stiller, C. A., Draper, G. J. & Bieber C. A. The international incidence of childhood cancer (IARC Scientific Publications). Int. J. Cancer 42, 511–520 (1988).
2. Linabery, A. M. & Ross, J. A. Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer 112, 416–432 (2008).
3. Pui, C. H., Yang, J. J., Bhakta, N. & Rodriguez-Galindo, C. Global efforts toward the cure of childhood acute lymphoblastic leukaemia. Lancet Child Adolesc. Health 2, 440–454 (2018).
4. Martin-Lorenzo, A. et al. Infection exposure is a causal factor in B-cell precursor acute lymphoblastic leukemia as a result of Pax5-inherited susceptibility. Cancer Discov. 5, 1328–1343 (2015).
5. Dang, J. et al. PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia. Blood 125, 3609–3617 (2015).
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