Journalartikel

Autorenliste: Vicente-Duenas, Carolina; Janssen, Stefan; Oldenburg, Marina; Auer, Franziska; Gonzalez-Herrero, Ines; Casado-Garcia, Ana; Isidro-Hernandez, Marta; Raboso-Gallego, Javier; Westhoff, Philipp; Pandyra, Aleksandra A.; Hein, Daniel; Goessling, Katharina L.; Alonso-Lopez, Diego; De Las Rivas, Javier; Bhatia, Sanil; Javier Garcia-Criado, Francisco; Begona Garcia-Cenador, Maria; Weber, Andreas P. M.; Koehrer, Karl; Hauer, Julia; Fischer, Ute; Sanchez-Garcia, Isidro; Borkhardt, Arndt

Jahr der Veröffentlichung: 2020

Seiten: 2003-2017

Zeitschrift: Blood

Bandnummer: 136

Heftnummer: 18

ISSN: 0006-4971

eISSN: 1528-0020

Open Access Status: Green

DOI Link: https://doi.org/10.1182/blood.2019004381

Verlag: American Society of Hematology (ASH Publications)

Abstract: 
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.

Harvard-Zitierstil: Vicente-Duenas, C., Janssen, S., Oldenburg, M., Auer, F., Gonzalez-Herrero, I., Casado-Garcia, A., et al. (2020) An intact gut microbiome protects genetically predisposed mice against leukemia, Blood, 136(18), pp. 2003-2017. https://doi.org/10.1182/blood.2019004381

APA-Zitierstil: Vicente-Duenas, C., Janssen, S., Oldenburg, M., Auer, F., Gonzalez-Herrero, I., Casado-Garcia, A., Isidro-Hernandez, M., Raboso-Gallego, J., Westhoff, P., Pandyra, A., Hein, D., Goessling, K., Alonso-Lopez, D., De Las Rivas, J., Bhatia, S., Javier Garcia-Criado, F., Begona Garcia-Cenador, M., Weber, A., Koehrer, 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