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Published on: December 4, 2018
Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response
Le Zhang1,2, Matthias Wirth1,2,3, Upayan Patra4
1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Abstract:
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.
Insights
Scientists found that SLF2 deficiency impairs DNA damage response (DDR) in B-cell lymphoma, leading to tumor growth. Targeting DDR and SUMOylation pathways together shows promise for treating aggressive lymphoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The DNA damage response (DDR) is crucial for preventing cancer, but its impairment is common in tumorigenesis.
- Understanding DDR inactivation mechanisms and biomarkers is key for developing effective cancer therapies.
- B-cell lymphoma (BCL) often involves impaired DDR, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify novel regulators and biomarkers of DDR in B-cell lymphoma.
- To investigate the therapeutic potential of targeting DDR and SUMOylation pathways in BCL.
Main Methods:
- Unbiased screening to identify DDR regulators.
- In vivo genetic deletion studies in mouse models.
- Analysis of DNA damage, DDR factor localization, and SUMOylation pathways.
- Evaluation of therapeutic efficacy of SUMOylation inhibitors (SUMOi) and DDR inhibitors.
Main Results:
- SMC5-SMC6 Complex Localization Factor 2 (SLF2) was identified as a DDR regulator and a biomarker for aggressive BCL.
- SLF2 deficiency impairs DDR by reducing Claspin levels and CHK1 activation, driving lymphomagenesis.
- SLF2-deficient tumors exhibit high DNA damage, leading to SUMOylation pathway alterations.
- Combined inhibition of DDR and SUMOylation pathways demonstrates synthetic lethality and synergistic effects.
Conclusions:
- SLF2 is a critical regulator of DDR and a prognostic biomarker in BCL.
- Co-targeting the DDR and SUMOylation pathways represents a promising therapeutic strategy for aggressive BCL.
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