In the absence of natural infection, pB-ALL development can be triggered by cooperation between a genetic predisposition and microbiome changes. Left panel: in WT mice, a short-term depletion of bacteria in the gut microbiome using antibiotic treatment led to a transient effect on the immune system (including the gut-associated and peripheral lymphoid tissues). In this scenario, mice do not develop pB-ALL. Right panel: the Pax5 mutation altered the microbiome composition and affected B-cell maturation. The dysbiosis translated into an altered plasma metabolome. In the absence of a natural infectious environment, untreated Pax5^+/– mice did not develop leukemia. However, in response to a transient depletion of the bacteria in the microbiome at age 8 weeks, pB-ALL was induced in 48% of the mice between age 11 and 21 months. Leukemia development was preceded by more prominent effects on the immune system¹³  and was associated with an altered plasma metabolome.