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Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage Response

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 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 the treatment of aggressive lymphoma.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture

SUBMITTER: Stefan Müller

LAB HEAD: Stefan Müller

PROVIDER: PXD041834 | Pride | 2023-07-21

REPOSITORIES: Pride

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Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage Response

Project description: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 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 the treatment of aggressive lymphoma.

2023-07-21 | PXD041851 | Pride

Actionable genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma

Project description:SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we identified the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to PARP inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.

2021-07-16 | GSE180052 | GEO

SUMO pulldown proteomics Namalwa 5-Aza-2' deoxycytidine treatment

Project description:Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2’-deoxycytidine (5-Aza-2’) enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2’ to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2’. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2’ (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. In contrast, single dosing of TAK981 was ineffective and single dosing of 5-Aza-2’ only led to a modest outgrowth reduction. TAK981 and 5-Aza-2’ synergize to reduce B cell Lymphoma outgrowth in vitro and in vivo. SUMOylation is a key-player in the repair of DNA damage, hence upon TAK981 treatment the repair of DNA damage induced by 5-Aza-2’ treatment is impaired. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.

2023-03-17 | PXD038620 | Pride

SUMO pulldown, U2OS, proteomics, 4 hour 20 hour 5-Aza-2' deoxycytidine treatment

2023-03-17 | PXD038617 | Pride

Unrestricted SUMOylation drives lymphomagenesis

Project description:Unrestricted SUMOylation drives lymphomagenesis

| PRJNA595164 | ENA

Unrestricted SUMOylation drives lymphomagenesis

Project description:Unrestricted SUMOylation drives lymphomagenesis

2021-10-11 | GSE141913 | GEO

RNA Sequencing Analysis of control vs KDM4Ai treated cells as a monotherapy or in combination with PARPi

Project description:Leukaemic blasts share common pathological features with other cancers including genome instability and impaired DNA damage response and repair (DDR). The limited efficacy of DDR inhibitors, such as poly (ADP-ribose) polymerase inhibitors (PARPi) as single agents in acute myeloid leukaemia (AML) is partly owing to activation of alternative DDR pathways and cytotoxicity to healthy tissues. Their strengths may lie in combination strategies targeting other essential proteins required for leukaemogenesis. We have identified the histone demethylase, KDM4A, as a critical epigenetic regulator required for AML cell survival. Depletion of KDM4A causes aberrant DDR pathway activation and subsequent DNA damage. We hypothesised that KDM4A inhibitors (KDM4Ai) increase AML cell reliance on specific DDR pathways for survival and may sensitise them to PARPi. We aimed to analyse transcriptional profiling (RNA Seq) changes associated with varying concentrations of KDM4A inhibition in monotherapy and as a combination therapy with a single PARPi treatment following 36hrs treatment. In summary, our study identifies a novel potential therapeutic strategy for AML. KDM4Ai sensitises cells to PARPi through impairing further NHEJ repair and enhancing PARP trapping leading to selective leukaemic cell death. These results warrant future clinical evaluation of this promising combination strategy in AML and other cancers.

2022-12-31 | GSE164437 | GEO

Altered levels of MOF and decreased levels of H4K16ac correlate with a defective DNA damage response (DDR).

Project description:Full title: Altered levels of MOF (member of MYST family histone acetyl transferase) and decreased levels of H4K16ac correlate with a defective DNA damage response (DDR). The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that altered levels of H4K16ac correlate with a defective DNA damage response (DDR) to ionizing radiation (IR). The defect however is not due to altered expression of proteins involved in DDR. Specific inhibition of H4K16ac deacetylation in MOF-depleted cells rescued IR-induced abrogation of DDR. MOF was found associated with DNA-dependent protein kinase catalytic subunit (DNAPKcs), a protein involved in non-homologous end joining (NHEJ) repair, whose ATMdependent IR-induced phosphorylation was abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased the repair of DNA double-strand breaks (DSBs) by NHEJ and homologous recombination (HR). In addition, the MOF protein activity associates with chromatin upon DNA damage and colocalizes with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac, plays a critical role in the cellular DNA damage response. Keywords: Cell type comparison HEK293 cells were transfected with plasmids encoding hMOF for over-expression of the histone acetyl transferase that leads to elevated levels of acetylation of Lysine 16 of histone H4. siRNA mediated knock-down of hMOF was performed to deplete the H4K16ac levels. Total RNA samples for expression profiling was obtained from wild type (293 cells without any treatment), hMOF over-expressed and hMOF knock-down 293 cell lines. Each sample was analyzed in triplicates using EGPF dsRNA treated samples as control.

2010-03-23 | E-GEOD-20193 | biostudies-arrayexpress

Expression data of Schizosaccharomyces pombe deletions involved in DNA damage response

Project description:DNA damage response (DDR) plays pivotal roles in maintaining genome integrity and stability. An effective DDR requires the involvement of hundreds of genes that compose a complicated network. To identify novel genes involved in DDR, we screened a genome-wide Schizosaccharomyces pombe (S. pombe) haploid deletion library against six different DNA damage reagents. We identified 52 genes that were actively involved in DDR. Among the 52 genes, 20 genes were linked to DDR for the first time. For a better understanding of DDR genes function, we performed a DNA microarray assay to analyze the gene expression profiles of eight deletions. Cells of wild type and eight deletions involved in DDR were collected during the expontentially growing stage, and were subjected to RNA extraction and hybridization on Affymetrix microarrays. We tried to understand the role of genes in DDR by comparing the expression profiles of deletions with that of wild type.

2012-09-11 | E-GEOD-40747 | biostudies-arrayexpress

DNA damage responsive microRNAs misexpressed in human cancer regulate chemotherapy sensitivity (lung cancer cell lines)

Project description:The DNA damage response (DDR) is a cellular process that protects the genetic information against DNA damage and inhibits malignant transformation. Tumor cells are characterized by an aberrant DDR, which is exploited by genotoxic chemotherapy. However, cancer cells are able to develop drug resistance, for example by modulation of the DDR. Although the regulation of the DDR has been extensively studied, not much is known about the role of microRNAs (miRNAs). Here, we describe an approach to specifically identify DDR miRNAs in human primary epithelial cells that also play a role in tumorigenesis and response to cancer therapy in corresponding cancer cells. The miRNA expression profile was determined of 12 lung cancer cell lines.

2013-05-31 | E-GEOD-47524 | biostudies-arrayexpress

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