Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response

The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5‐SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B‐cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2‐deficiency leads to loss of DDR factors including Claspin (CLSPN) and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo . Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post‐translational SUMOylation pathway as a safeguard. The resulting co‐dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co‐targeting of the DDR and SUMOylation as a promising strategy for treating aggressive lymphoma. Synopsis SLF2 was identified as a tumor suppressor of B‐cell lymphomagenesis and a crucial regulator of CHK1, and its deficiency was associated with defective DNA damage response and synthetic lethality to SUMOylation inhibition. SLF2 is a functionally relevant tumor suppressor in murine and human B‐cell lymphoma. Loss of SLF2 results in CHK1 impairment, transcriptional or post‐transcriptional repression of Claspin, and genomic instability. SLF2 deficiency drives alteration of the SUMO pathway and confers synthetic lethality to pharmacological SUMOylation inhibition. Impaired DNA damage responses, e.g., caused by SLF2 loss or pharmacological inhibition of CHK1, confer synthetic lethality to SUMO inhibition. Graphical Abstract SLF2 was identified as a tumor suppressor of B‐cell lymphomagenesis and a crucial regulator of CHK1, and its deficiency was associated with defective DNA damage response and synthetic lethality to SUMOylation inhibition.