Similar Datasets
Project description:Unrestricted SUMOylation drives lymphomagenesis
| PRJNA595164 | ENA
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
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 | PXD041834 | Pride
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
Project description:Histone 1 deficiency drives lymphomagenesis through disruption of 3D chromatin architecture
| PRJNA599930 | ENA
Project description:A SUMOylation-induced Satb1/Satb2 switch drives embryonic stem cell differentiation
| PRJNA490897 | ENA
Project description:Aberrant activation of NF-κB transcription factors is a hallmark of human lymphoma. Many lymphoma- as well as microenvironment-associated alterations mediating enhanced NF-κB signaling occur upstream of the IκB Kinase complex and its key kinase IKK2, therefore affecting additional pathways. Here, we specifically investigated the effects of graded canonical NF-κB activation in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant (IKK2ca). Strong canonical NF-κB signaling drives an early expansion of B1a cells, culminating in lethal lymphomagenesis with complete penetrance. These B cell malignancies resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) with respect to disease course, gene expression and stereotypic B cell receptor clonality. Mice with less pronounced canonical NF-κB activation presented delayed, more heterogeneous lymphomagenesis with lower penetrance, highlighting NF-κB dose-dependent effects. Mechanistically, we show that constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and strongly synergize with TCL1 overexpression, resulting in a severely accelerated and aggravated CLL-like disease. In addition, strong constitutive NF-κB activation overcomes the critical dependency of TC1tg lymphoma cells on obligate environmental maintenance signals. In conclusion, we provide direct in vivo proof for canonical NF-κB signals as an oncogenic driver in an animal model, and demonstrate reduced tumor microenvironment dependency as a key NF-κB-mediated mechanism in lymphomagenesis. Our findings underscore the pivotal role of this pathway in human SLL/CLL and its potential as a therapeutic target, particularly for aggressive/refractory disease.
2026-03-11 | GSE289013 | GEO
Project description:Aberrant activation of NF-κB transcription factors is a hallmark of human lymphoma. Many lymphoma- as well as microenvironment-associated alterations mediating enhanced NF-κB signaling occur upstream of the IκB Kinase complex and its key kinase IKK2, therefore affecting additional pathways. Here, we specifically investigated the effects of graded canonical NF-κB activation in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant (IKK2ca). Strong canonical NF-κB signaling drives an early expansion of B1a cells, culminating in lethal lymphomagenesis with complete penetrance. These B cell malignancies resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) with respect to disease course, gene expression and stereotypic B cell receptor clonality. Mice with less pronounced canonical NF-κB activation presented delayed, more heterogeneous lymphomagenesis with lower penetrance, highlighting NF-κB dose-dependent effects. Mechanistically, we show that constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and strongly synergize with TCL1 overexpression, resulting in a severely accelerated and aggravated CLL-like disease. In addition, strong constitutive NF-κB activation overcomes the critical dependency of TC1tg lymphoma cells on obligate environmental maintenance signals. In conclusion, we provide direct in vivo proof for canonical NF-κB signals as an oncogenic driver in an animal model, and demonstrate reduced tumor microenvironment dependency as a key NF-κB-mediated mechanism in lymphomagenesis. Our findings underscore the pivotal role of this pathway in human SLL/CLL and its potential as a therapeutic target, particularly for aggressive/refractory disease.
2026-03-11 | GSE289016 | GEO
Project description:A SUMOylation-induced Satb1/Satb2 switch drives embryonic stem cell differentiation [HiC]
| PRJNA641396 | ENA
Project description:To gain insight into the impact of THO complex sumoylation on gene expression in yeast S. cerevisiae, total RNAs were extracted from wt and hpr1-KR cells and transcriptome profiles were analyzed by Agilent microarrays. The hpr1 K-R mutant is a version of the hpr1 THO subunit in which lysines 60-65 were simultaneously mutated, which abrogated the sumoylation of the protein.
2014-01-25 | E-MTAB-2138 | biostudies-arrayexpress