TY - JOUR
T1 - Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID
AU - Rodríguez-Hernández, Guillermo
AU - Opitz, Friederike V.
AU - Delgado, Pilar
AU - Walter, Carolin
AU - Álvarez-Prado, Ángel F.
AU - González-Herrero, Inés
AU - Auer, Franziska
AU - Fischer, Ute
AU - Janssen, Stefan
AU - Bartenhagen, Christoph
AU - Raboso-Gallego, Javier
AU - Casado-García, Ana
AU - Orfao, Alberto
AU - Blanco, Oscar
AU - Alonso-López, Diego
AU - Rivas, Javier De Las
AU - Tena-Dávila, Sara González de
AU - Müschen, Markus
AU - Dugas, Martin
AU - Criado, Francisco Javier García
AU - Cenador, María Begoña García
AU - Vicente-Dueñas, Carolina
AU - Hauer, Julia
AU - Ramiro, Almudena R.
AU - Sanchez-Garcia, Isidro
AU - Borkhardt, Arndt
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076017642&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-13570-y
DO - 10.1038/s41467-019-13570-y
M3 - Article
C2 - 31804490
AN - SCOPUS:85076017642
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5563
ER -