An intact gut microbiome protects genetically predisposed mice against leukemia

Abstract

The majority of childhood leukemias are precursor B cell-acute lymphoblastic leukemias (pB-ALL) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1-5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. While infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, employing 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. Using V4 and full-length 16S rRNA 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 3,983 amplicon sequence variants (ASVs) 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 spectrometric (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.

IRF4 deficiency vulnerates B progeny for leukemogenesis via Jak3 mutations resembling Ph-like B-ALL in humans

“…Taken together, our study stresses the general vulnerability of pro/preB cells to immortalization. Secondary steps for mutagenesis may include infectious agents as recently found empirically in the Pax5 +/model 69 and also supported by our finding of Aicda upregulation by LPS.…”

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

“…This aspect is particularly important for the evolution from pre-leukemia to B-ALL. It has recently been shown in murine models of B-ALL that disruption of the microbiome by antibiotic administration in pre-leukemic mice in the first weeks of life was sufficient to induce leukemia [ 57 ]. Although it is not yet clear what are the mechanisms underlying the interplay between microbiome, pre-leukemic cell, and tumor transformation, these studies open new scenarios on the possibility of acting on the microbiome to develop effective strategies for preventing the development of overt leukemia ( Figure 1 C).…”

Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

“…Host microbiome is also rapidly emerging as a predictor of severity and therapy outcomes in several incidences of cancers (Poore et al, 2020;Zhuang et al, 2019). Numerous studies have shown altered gut microbioata composition during the development of various cancers including but not limited to colorectal cancer (Nakatsu et al, 2015), gastric cancer (Ferreira et al, 2018), lung cancer (Zhuang et al, 2019), pancreatic cancer (Half et al, 2019), prostate cancer (Daisley et al, 2020), breast cancer (Goedert et al, 2015), brain cancer (D'Alessandro et al, 2020) and even leukemia (Vicente-Dueñas et al, 2020). Mechanistically, the gut microbiome can influence tumorigenesis at sites distant to the gut by regulating circulatory levels of metabolites and nutrients as well as through the release of microbial toxins which are currently under intense investigation (Parida and Sharma, 2021).…”