Enhancer engagement sustains oncogenic transformation and progression of B-cell precursor acute lymphoblastic leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214916 | GEO | 2024/06/27
REPOSITORIES: GEO
Similar Datasets
Project description:Enhancer engagement sustains oncogenic transformation and progression of B-cell precursor acute lymphoblastic leukemia
| PRJNA887733 | ENA
Project description:Activation of mostly quiescent hematopoietic stem cells (HSC) is a prerequisite for life-long blood production1, 2. This process requires major molecular adaptations to meet the regulatory and metabolic requirements for cell division3-8. The mechanisms governing cellular reprograming upon stem cell activation and their subsequent return to quiescence are still not fully characterized. Here, we describe a role for chaperone-mediated autophagy (CMA)9, a selective form of lysosomal protein degradation, in sustaining adult HSC function. CMA is required for stem cell protein quality control and upregulation of fatty acid metabolism upon HSC activation. We identify that CMA activity decreases with age in HSC and show that genetic or pharmacological activation of CMA can restore functionality of old HSC. Together, our findings provide mechanistic insights into a new role for CMA in sustaining quality control, appropriate energetics and overall long-term hematopoietic stem cell function. Our work supports that CMA may be a promising therapeutic target to enhance hematopoietic stem cell function in conditions such as aging or stem cell transplantation.
2021-03-05 | PXD022196 | Pride
Project description:Acute lymphoblastic leukemia (ALL) is characterized by the accumulation of somatic genetic alterations in B- or T-lymphoid precursor cells eventually resulting in overt leukemia. We characterized somatic events associated with leukemic transformation by detailed genome-wide copy number analyses of 53 adult B-cell acute lymphoblastic leukemia (B-ALL) and, 20 adult T-cell ALL (T-ALL) cases by comparing to matched control remission specimens. Contrary the paediatric counterpart, adult ALL is scarcely researched in terms of genetic events. We initiated this study to examine whether there are differences in genetic events between paediatric and adult ALL and to observer whether these genetic lesions are driven by aberrant RAG activity. This submission of 53 adult B-ALL and 20 adult T-ALL, with 73 matched control remission material, characterized on the Affymetrix GeneChip Genome-Wide Human SNP 6.0 serves as a repository for multiple studies examining the leukemogenic mechanisms underlying overt ALL establishment. The Affymetrix GeneChip Genome-Wide Human SNP 6.0 was utilized due to its capability to detect copy number variations (CNVs) with high resolution in conjunction to determining genotypes. After informed consent, bone marrow aspirates or peripheral blood samples of a representative cohort of 73 adult ALL patients were collected. Eligible patients had a diagnosis of primary ALL confirmed by cytological examination and immunophenotyping of blood and bone marrow. The majority of these cases were treated following the HOVON (Dutch-Belgian Hematology-Oncology Co-operative group) protocols (http://www.hovon.nl). All studies were approved through the institutional ethics review board and all patients provided written informed consent in accordance to the declaration of Helsinki.<br>Complementary expression profiling data from the same study have also been deposited at ArrayExpress, under accession number E-MTAB-5035 ( http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5035/ ). A supplementary file 'DNA_RNA_link_numbers.xlsx' is also provided allowing DNA samples in this submission to be mapped against equivalent RNA sample in E-MTAB-5035.</br>
2017-01-31 | E-MTAB-5036 | biostudies-arrayexpress
Project description:Identification of de novo copy number abnormalities arising in relapsed paediatric ALL in matched presentation and relapse samples. We identified deletions of BACH2, (BTB and CNC homology 1, basic leucine zipper transcription factor 2) at relapse. To study the role of Bach2 in pre-B ALL in a genetic experiment, we transformed pre-B cells from Bach2–/– mice with BCR-ABL1. Our findings identify Bach2 as a novel tumor suppressor upstream of p53 in pre-B ALL. 64 arrays (32 250K Nsp and 32 250K Sty) are included in this study. DNA was extracted from the presentation and relapse samples from 11 paediatric patients and DNA was extarcted from the remission samples from 10 patient and hybridised to the Affymetrix Human Mapping 500K Array Set.
2013-12-21 | E-GEOD-43060 | biostudies-arrayexpress
Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
2021-06-07 | GSE100646 | GEO
Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
2021-06-07 | GSE100494 | GEO
Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
2021-06-07 | GSE100493 | GEO
Project description:Identification of de novo copy number abnormalities arising in relapsed paediatric ALL in matched presentation and relapse samples. We identified deletions of BACH2, (BTB and CNC homology 1, basic leucine zipper transcription factor 2) at relapse. To study the role of Bach2 in pre-B ALL in a genetic experiment, we transformed pre-B cells from Bach2–/– mice with BCR-ABL1. Our findings identify Bach2 as a novel tumor suppressor upstream of p53 in pre-B ALL.
2013-12-21 | GSE43060 | GEO
Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous disease that can be subdivided according to primary recurrent genetic abnormalities that are strongly associated with characteristic biological and clinical features. The detection of these abnormalities can facilitate diagnosis, risk stratification, and targeted therapy. We identified an unexpectedly high incidence of fusion genes involving ZNF384 genes, including TCF3-ZNF384, EP300-ZNF384, and CREBBP-ZNF384, in BCP-ALL of our cohort. We therefore used microarrays to evaluate the gene-expression characteristics of BCP-ALL harboring ZNF384-related fusion genes and compared with those of BCP-ALL with other types of conventional genetic abnormality.
2017-03-21 | GSE79533 | GEO
Project description:Premature senescence-associated functional decay and neoplastic transformation of transplanted human stem cells or their derivatives represent two major roadblocks for regenerative medicine. Cellular senescence acts as a major mechanism antagonizing neoplastic transformation, and stem cells evading senescence are prone to oncogenic transformation. So far it is unknown whether there is any genetic code, rewriting of which can simultaneously brake cellular senescence and oncogenic transformation programs. Here, we identify a single nucleotide in human genome(target on the transcription factor NRF2) as a candidate code, switch of which blocks both senescence and transformation pathways. Genetic modification stabilizes the wild type human mesenchymal stem cells (hMSCs) at a “sustainably younger” state. More importantly, the same genetic manipulation endows hMSCs with the ability of counteracting oncogenic transformation. Our study thus provides the first proof-of-concept of genetic enhancement of human stem cells, a strategy holding potential to generate superior and safer stem cell materials for cell replacement therapy.
2017-07-21 | GSE84694 | GEO