Proposed mechanism of SHMT2 inhibition on BL cells with oncogenic TCF3 signaling. (A) Aberrant activity of TCF3 leads to activation of the PI3K pathway which promotes survival of BL cells. SHMT2 is involved in the production of glycine and formate which are required for BL cell growth; the mTOR pathway senses nutrient availability, and under nutrient-rich conditions, it inhibits autophagy. (B) Drug-mediated inhibition of SHMT2 impairs the synthesis of glycine and formate. The resulting decrease in the intracellular concentrations of these metabolites leads to inhibition of the mTOR pathway whose blockade induces the establishment of autophagosomes in which TCF3 is degraded. The inactivation of oncogenic TCF3 alleviates PI3K signaling, leading to BL cell death.