Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Blood. 2020 Oct 29;136(18):2003-2017. doi: 10.1182/blood.2019004381.
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 Pax5+/- 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 Pax5+/- 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.
大多数儿童白血病是前体 B 细胞急性淋巴细胞白血病 (pB-ALL)，由产前遗传易感性和出生后致癌事件的组合引起。尽管遗传易感性在儿童中很常见（>1%至 5%），但只有不到 1%的遗传易感性携带者会发展为 pB-ALL。虽然感染性刺激被认为在白血病发生中起主要作用，但关键决定因素尚未明确。在这里，我们使用 pB-ALL 的小鼠模型表明，生命早期抗生素治疗引起的微生物组紊乱足以诱导遗传易感小鼠发生白血病，即使在没有感染性刺激且独立于 T 细胞的情况下也是如此。通过对一系列粪便样本进行 V4 和全长 16S 核糖体 RNA 测序，我们发现 pB-ALL 的遗传易感性（Pax5 杂合性或 ETV6-RUNX1 融合）塑造了独特的肠道微生物组。机器学习使用 3983 个扩增子序列变体中的 40 个作为细菌物种的代表，可以准确（96.8%）预测遗传易感性。将野生型（WT）或 Pax5+/-造血骨髓细胞移植到 WT 受体小鼠中表明，微生物组以供体基因型特异性的方式形成和确定。WT 和 Pax5+/-小鼠血清的气相色谱-质谱（GC-MS）分析表明存在基因型特异性的独特代谢组学特征。总之，我们的数据表明，促进遗传易感小鼠发生白血病的是缺乏共生微生物群，而不是特定细菌的存在。需要进行大规模的纵向研究，以确定针对易患 pB-ALL 的儿童进行靶向微生物组修饰是否可以成为一种成功的预防策略。
