期刊
BLOOD
卷 136, 期 18, 页码 2003-2017出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019004381
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资金
- FEDER, Miguel Servet Grant from the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad), Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III [CP14/00082-AES 2013-2016, PI17/00167]
- ERAPer Med GEPARD
- German Cancer AID (Translational Oncology Program) [70112951]
- ERCStg [85222]
- German Jose Carreras Foundation [DJCLS 02R/2016, 07R/2019]
- Kinderkrebsstiftung (2016/17)
- Katharina-Hardt-Stiftung
- German Children's Cancer Foundation
- Federal Ministry of Education and Research, Bonn, Germany
- Junta de Castilla y Leon [UIC-017, CSI001U16, CSI234P18]
- European Union under the FP7 program
- German Carreras Foundation [DJCLS R13/26, DJCLS 21R/2019]
- German Federal Office for Radiation Protection (BfS) [FKZ: 3618S32275, 3618S32274, FKZ: 3618S32274]
- Research Commission of the Medical Faculty of the Heinrich-Heine-University of Dusseldorf [2016/70, 2019/03]
- German Research Foundation (DFG) under Germany's Excellence Strategy [EXC2048/1, 390686111]
- [SAF2015-64420-R]
- [RTI2018-093314-B-I00]
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.
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