SHMT2 controls Burkitt lymphoma cell survival by maintaining an oncogenic TCF3 transcriptional program

Chemotherapy-related toxicity and disease relapse are major clinical challenges in Burkitt lymphoma (BL). Hence, there is a clinical need for new therapeutic strategies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators and one-carbon metabolism as vulnerabilities in BL. Given the known clinical efficacy of Methotrexate (MTX), a folate antagonist, in BL treatment, we further focused on one -carbon metabolism by investigating the function of serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in this pathway, for which compounds that inhibit its enzymatic function have already been developed. As a model, we used Burkitt lymphoma cell lines (e.g. BL60) that were transduced with constitutively active or Doxycycline-inducible short-hairpin RNAs (shRNAs) to knockdown SHMT2 or treated with the commercially available SHMT inhibitor SHIN1 to functionally elucidate the consequences of SHMT2 downregulation or enzymatic inhibition.