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Título
An intact gut microbiome protects genetically predisposed mice against leukemia
Autor(es)
Assunto
Acute Lymphoblastic-Leukemia
Childhood Leukemia
Gene-Expression
Cancer
Adult
Trends
Patterns
Risk
Clasificación UNESCO
3201.01 Oncología
Fecha de publicación
2020
Editor
American Society of Hematology
Citación
Vicente-Dueñas, C., Janssen, S., Oldenburg, M., Auer, F., González-Herrero, I., Casado-García, A., Isidro-Hernández, M., Raboso-Gallego, J., Westhoff, P., Pandyra, A. A., Hein, D., Gössling, K. L., Alonso-López, D., De Las Rivas, J., Bhatia, S., García-Criado, F. J., García-Cenador, M. B., Weber, A. P. M., Köhrer, K., … Borkhardt, A. (2020). An intact gut microbiome protects genetically predisposed mice against leukemia. Blood, 136(18), 2003-2017. https://doi.org/10.1182/blood.2019004381
Resumen
[EN]The majority of childhood leukemias are precursor B-cell acute lymphoblastic leukemias (pB-ALLs) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1% to 5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. Although infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, by using murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice, even in the absence of infectious stimuli and independent of T cells. By using V4 and full-length 16S ribosomal RNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3983 amplicon sequence variants as proxies for bacterial species. Transplantation of either wild-type (WT) or Pax51/- hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor genotype-specific manner. Gas chromatography-mass spectrometry (GC-MS) analyses of sera from WT and Pax51/- mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.
URI
ISSN
0006-4971
DOI
10.1182/BLOOD.2019004381
Versión del editor
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