Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs CHK1 mediated DNA repair. SLF2 in DLBCL

The DNA damage response (DDR) acts as barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the defective DDR can be a promising therapeutic strategy, however, the mechanisms of inactivation and corresponding biomarkers are not well understood. Starting from an unbiased screening, we identified the SMC5-SMC6 Complex Localization Factor 2 (SLF2) as regulator of the ATR-CHK1 pathway and biomarker for a DLBCL patient subgroup with adverse prognosis. SLF2 deficiency leads to loss of CLSPN and consequently impairs CHK1 activation in response to DNA damage stress. Accordingly, genetic deletion of Slf2 drives B-cell lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which activates the post-translational SUMOylation pathway. Of note, this tight association confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi) and inhibitors of the DDR pathway (DDRi) act highly synergistic with SUMOi. Together, our results identify SLF2 as regulator of the ATR-CHK1 pathway and reveal co-targeting of the DDR and SUMOylation as promising clinical strategy for the treatment of aggressive human cancers.