BMF repression keeps mitosis away from anoikis
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB44770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5883370.fastq.gz | Fastqsanger.gz | |||
| ERR5883371.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for the survival of the plasma cell malignancy multiple myeloma (MM), although the mechanism by which this is achieved remains unknown. Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 genetic ablation of IRF4 across several MM cells lines. We report that IRF4 loss uniformly resulted in the upregulation of two related pro-apoptotic proteins belonging to the BH3-only subgroup of the BCL2 family: BCL2 modifying factor (BMF) and BCL2 interacting mediator of cell death (BIM). Direct IRF4 binding was identified in the proximal promoter region of both genes. Remarkably, genetic ablation of BMF alone or in combination with BIM largely prevented the cell death that follows IRF4 inactivation, establishing that IRF4 maintains MM survival through the direct transcriptional repression of BMF and BIM.
2022-12-22 | GSE148984 | GEO
Project description:Suspension-induced cell death, or anoikis, is implicated in different stages of breast development as well as tumor progression and metastasis. The pro-apoptotic BH3-only proteins BIM and BMF are known positive regulators of anoikis. We examined the gene expression changes that occur in BIM-/- BMF-/- cells during attachment and suspension. This study is supplemental to our work establishing a role for JNK in anoikis (Girnius N, Davis RJ. 2017. JNK promotes epithelial cell anoikis by transcriptional and post-translational regulation of BH3-only proteins. (2017) Cell Reports 21: 1910-1921; doi: 10.1016/j.celrep.2017.10.067)
2018-02-28 | GSE111221 | GEO
Project description:Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.
2026-03-12 | GSE305428 | GEO
Project description:Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.
2026-03-12 | GSE305437 | GEO
Project description:Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.
2026-03-12 | GSE305435 | GEO
Project description:Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.
2026-03-12 | GSE305430 | GEO
Project description:Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.
2026-03-12 | GSE305431 | GEO
Project description:Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK-deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that JNK acts through a BAK/BAX-dependent apoptotic pathway by increasing BIM expression and phosphorylating BMF leading to death of detached epithelial cells.
2017-11-14 | GSE88856 | GEO
Project description:We performed bulk RNA sequencing of bone marrow CD8+ T cells in bone marrow failure (BMF) mice treated with or without baricitinib (BAR) at day 10 and day 14 post BMF induction to investigate the time-dependent gene expression changes of T cells induced by JAK1/2 inhibition (BAR).
2026-03-11 | GSE293533 | GEO
Project description:Proper chromosome segregation is required to ensure genomic and chromosomal stability. The centromere is a unique chromatin domain present throughout the cell cycle on each chromosome defined by the CENP-A nucleosome. Centromeres (CEN) are responsible for recruiting the kinetochore (KT) during mitosis, ultimately regulating spindle attachment and mitotic checkpoint function. Upregulation of many genes that encode CEN/KT proteins is commonly observed in cancer. Here, we show although FOXM1 occupies the promoters of many CEN/KT genes with MYBL2, occupancy is insufficient alone to drive the FOXM1 correlated transcriptional program. We show that CENP-F, a component of the outer kinetochore, functions with FOXM1 to coregulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in alteration of chromatin accessibility at G2/M genes, including CENP-A, and leads to reduced FOXM1-MBB complex formation. The FOXM1-CENP-F transcriptional coordination is a cancer-specific function. We observed that a few CEN/KT genes escape FOXM1 regulation such as CENP-C which when upregulated with CENP-A, leads to increased chromosome misegregation and cell death. Together, we show that the FOXM1 and CENP-F coordinately regulate G2/M gene expression, and this coordination is specific to a subset of genes to allow for proliferation and maintenance of chromosome stability for cancer cell survival.
2024-06-01 | GSE252505 | GEO