Whole transcriptome and exome sequencing of childhood ALL
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ABSTRACT:
PROVIDER: EGAS00001001858 | EGA |
REPOSITORIES: EGA
Similar Datasets
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:We found that the bone marrow microenvironment of Crebbp+/- mice was unable to properly maintain the immature stem - and progenitor pools. Instead, it stimulates myeloid differentiation that progresses into a myeloproliferative-like disease. Since CREBBP is a transcriptional co-activator, we used gene expression analysis to globally assess functional deficiencies in Crebbp+/- bone marrow stroma cells at a molecular level. Ep300 encodes a protein which is highly similar in structure and function to CREBBP; nevertheless, Ep300+/- mice suffer neither excessive myeloid differentiation nor loss of HSCs. Therefore, to identify expression changes specifically related to Crebbp heterozygosity, we focused on genes that showed significant differences in expression levels between Crebbp+/- and wild-type bone marrow stroma but no difference between Ep300+/- and wild-type. Bone marrow stroma was established from wild-type, Crebbp+/- and Ep300+/- mice that were 3-4 months old for RNA extraction and hybridization on Affymetrix microarrays. There are 4 biological replicates for each genotype used.
2011-03-01 | E-GEOD-24773 | biostudies-arrayexpress
Project description:Antiprolifereative effects of CREBBP/EP300 inhibitors were tested in human leukemia and lymphoma cell lines and the molecular mechanisms responsible for such effects were explored.
2018-06-12 | GSE77295 | GEO
Project description:ZNF384-rearranged fusion oncoproteins (FO) define a subset of lineage ambiguous leukemias, but the mechanistic role of ZNF384 FO in leukemogenesis and lineage ambiguity is poorly understood. Here, using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPCs) and a Ep300-Zfp384 mouse model we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal. In mouse HSPCs, concomitant lesions such as NRASG12D, were required for fully penetrant leukemia, whereas expression of ZNF384 FO drove development of B/myeloid leukemia in human HSPCs, with sensitivity of human ZNF384r leukemia to FLT3 inhibition in vivo. Mechanistically, ZNF384 FO occupy a subset of predominantly intragenic/enhancer regions with increased histone 3 lysine acetylation suggesting enhancer function. These data define a paradigm for FO-driven lineage ambiguous leukemia, in which expression in HSPCs results in deregulation of lineage-specific genes and hematopoietic skewing, progressing to full leukemic transformation in the presence of proliferative stress.
2022-03-16 | PXD028481 | Pride
Project description:We found that the bone marrow microenvironment of Crebbp+/- mice was unable to properly maintain the immature stem - and progenitor pools. Instead, it stimulates myeloid differentiation that progresses into a myeloproliferative-like disease. Since CREBBP is a transcriptional co-activator, we used gene expression analysis to globally assess functional deficiencies in Crebbp+/- bone marrow stroma cells at a molecular level. Ep300 encodes a protein which is highly similar in structure and function to CREBBP; nevertheless, Ep300+/- mice suffer neither excessive myeloid differentiation nor loss of HSCs. Therefore, to identify expression changes specifically related to Crebbp heterozygosity, we focused on genes that showed significant differences in expression levels between Crebbp+/- and wild-type bone marrow stroma but no difference between Ep300+/- and wild-type.
2011-03-01 | GSE24773 | GEO
Project description:Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.
2021-06-01 | GSE124192 | GEO
Project description:Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.
2020-02-19 | GSE132365 | GEO
Project description:<p>Few genetic drivers of children with hyperdiploid precursor B-cell acute lymphoblastic leukemia (ALL) have been identified to date. In an effort to detect novel genomic rearrangements that could be promoting leukemogenesis in this subset of patients, we sequenced ribosomal RNA-depleted transcriptomes isolated from 5 hyperdiploid acute lymphoblastic leukemia samples. In addition to looking for novel genomic rearrangements, we also sought to identify transcripts that could be created as a result of a novel posttranscriptional process. Surprisingly, we identified transcripts created as the result of exon circularization. The results of our studies are present in the paper "Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types" published in PLoS ONE (PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/22319583" target="_blank">22319583</a>).</p>
| phs000522 | dbGaP
Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.
2020-01-29 | MSV000084862 | MassIVE