Rodriguez-Hernandez, Guillermo, Opitz, Friederike V., Delgado, Pilar ORCID: 0000-0002-8431-8002, Walter, Carolin, Alvarez-Prado, Angel F., Gonzalez-Herrero, Ines, Auer, Franziska, Fischer, Ute, Janssen, Stefan ORCID: 0000-0003-0955-0589, Bartenhagen, Christoph, Raboso-Gallego, Javier ORCID: 0000-0002-7405-8999, Casado-Garcia, Ana ORCID: 0000-0003-1510-1499, 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 ORCID: 0000-0002-5401-8295, Hauer, Julia, Ramiro, Almudena R., Sanchez-Garcia, Isidro and Borkhardt, Arndt (2019). Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rodriguez-Hernandez, GuillermoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opitz, Friederike V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delgado, PilarUNSPECIFIEDorcid.org/0000-0002-8431-8002UNSPECIFIED
Walter, CarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvarez-Prado, Angel F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Herrero, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auer, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janssen, StefanUNSPECIFIEDorcid.org/0000-0003-0955-0589UNSPECIFIED
Bartenhagen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raboso-Gallego, JavierUNSPECIFIEDorcid.org/0000-0002-7405-8999UNSPECIFIED
Casado-Garcia, AnaUNSPECIFIEDorcid.org/0000-0003-1510-1499UNSPECIFIED
Orfao, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanco, OscarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alonso-Lopez, DiegoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Las Rivas, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez de Tena-Davila, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muschen, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dugas, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia Criado, Francisco JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia Cenador, Maria BegonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vicente-Duenas, CarolinaUNSPECIFIEDorcid.org/0000-0002-5401-8295UNSPECIFIED
Hauer, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramiro, Almudena R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Garcia, IsidroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borkhardt, ArndtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-124738
DOI: 10.1038/s41467-019-13570-y
Journal or Publication Title: Nat. Commun.
Volume: 10
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INDUCED CYTIDINE DEAMINASE; GENE-EXPRESSION; LYMPHOCYTIC-LEUKEMIA; GENOMIC INSTABILITY; SUPER-ENHANCERS; CANCER; ADULT; HYPERMUTATION; PAX5; SUSCEPTIBILITYMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12473

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