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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Vydané v:	Nature communications Ročník 10; číslo 1; s. 5563 - 10
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 05.12.2019 Nature Publishing Group Nature Portfolio
Predmet:	38/1 38/22 38/23 38/61 38/77 38/90 45 45/23 631/67/1990/283/2125 64 64/60 692/4028/67/1990/283/2125 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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-13570-y