An intact gut microbiome protects genetically predisposed mice against leukemia

Area of Science:

• Hematology
• Microbiology
• Genetics

Background:

• Childhood precursor B-cell acute lymphoblastic leukemia (pB-ALL) arises from genetic predispositions and postnatal events.
• While infectious stimuli are implicated, key leukemogenesis factors remain unclear.
• Genetic predisposition alone rarely leads to pB-ALL, indicating other critical determinants.

Purpose of the Study:

• To investigate the role of microbiome disturbances in pB-ALL development in genetically predisposed murine models.
• To determine if early-life antibiotic treatment, altering the gut microbiome, can induce leukemia.
• To explore the relationship between genetic predisposition, gut microbiome composition, and metabolic profiles.

Main Methods:

• Utilized murine models of pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion).
• Administered antibiotic treatment to induce microbiome disturbances.
• Performed 16S ribosomal RNA sequencing for microbiome analysis and machine learning for prediction.
• Conducted bone marrow transplantation experiments and gas chromatography-mass spectrometry (GC-MS) for metabolomic profiling.

Main Results:

• Antibiotic-induced microbiome disturbances were sufficient to induce pB-ALL in genetically predisposed mice, independent of T cells.
• Genetic predisposition shaped a distinct gut microbiome, accurately predicted by machine learning (96.8%).
• Microbiome composition was determined by donor genotype, and distinct genotype-specific metabolomic profiles were observed.

Conclusions:

• A lack of commensal microbiota, rather than the presence of specific bacteria, promotes leukemia in genetically predisposed mice.
• Findings highlight the critical role of the gut microbiome in pB-ALL pathogenesis.
• Targeted microbiome modification may offer a future prevention strategy for children at risk of pB-ALL.