Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID

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 evidenc...

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Veröffentlicht in:Nature communications Jg. 10; H. 1; S. 5563 - 10
Hauptverfasser: Rodríguez-Hernández, Guillermo, Opitz, Friederike V., Delgado, Pilar, Walter, Carolin, Álvarez-Prado, Ángel F., González-Herrero, Inés, Auer, Franziska, Fischer, Ute, Janssen, Stefan, Bartenhagen, Christoph, Raboso-Gallego, Javier, Casado-García, Ana, Orfao, Alberto, Blanco, Oscar, Alonso-López, Diego, Rivas, Javier De Las, Tena-Dávila, Sara González de, Müschen, Markus, Dugas, Martin, Criado, Francisco Javier García, Cenador, María Begoña García, Vicente-Dueñas, Carolina, Hauer, Julia, Ramiro, Almudena R., Sanchez-Garcia, Isidro, Borkhardt, Arndt
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 05.12.2019
Nature Publishing Group
Nature Portfolio
Schlagworte:
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Activation-induced cytidine deaminase
Acute lymphoblastic leukemia
Animals
B-Lymphocytes - metabolism
B-Lymphocytes - pathology
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Child
Children
Clonal deletion
Cytidine deaminase
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Etiology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic transformation
High-Throughput Nucleotide Sequencing - methods
Humanities and Social Sciences
Humans
Infections - genetics
Infections - physiopathology
Kaplan-Meier Estimate
Leukemia
Lymphatic leukemia
Lymphocytes B
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
multidisciplinary
Pax5 protein
PAX5 Transcription Factor - genetics
PAX5 Transcription Factor - metabolism
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Precursors
Science
Science (multidisciplinary)
ISSN:2041-1723, 2041-1723
Online-Zugang:Volltext
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Zusammenfassung: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. Infection or chronic inflammation is a risk factor for childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors show that the DNA editing enzyme AID is expressed in infected B cells but using genetic mouse models show that it does not contribute to leukemia pathogenesis.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-13570-y