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oai:gredos.usal.es:10366/1553522025-04-30T19:28:42Zcom_10366_3974com_10366_3947com_10366_3946com_10366_3823col_10366_3975

Vicente Dueñas, Carolina Janssen, Stefan Oldenburg, Marina Auer, Franziska González‐Herrero, Inés Casado García, Ana Isidro Hernández, Marta Raboso Gallego, Javier Westhoff, Philipp Pandyra, Aleksandra A. Hein, Daniel Gössling, Katharina L. Alonso López, Diego Rivas Sanz, Javier de las Bhatia, Sanil García Criado, Francisco Javier García Cenador, María Begoña Weber, Andreas P. M. Köhrer, Karl Hauer, Julia Fischer, Ute Sánchez García, Isidro Borkhardt, Arndt 2024-02-05T17:33:23Z 2024-02-05T17:33:23Z 2020 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 0006-4971 http://hdl.handle.net/10366/155352 10.1182/BLOOD.2019004381 1528-0020 [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. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional Acute Lymphoblastic-Leukemia Childhood Leukemia Gene-Expression Cancer Adult Trends Patterns Risk An intact gut microbiome protects genetically predisposed mice against leukemia info:eu-repo/semantics/article