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Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation

ABSTRACT: Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation

PROVIDER: PRJNA1263563 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33591700_1.fastq.gz	Fastqsanger.gz
	SRR33591700_2.fastq.gz	Fastqsanger.gz
	SRR33591701_1.fastq.gz	Fastqsanger.gz
	SRR33591701_2.fastq.gz	Fastqsanger.gz
	SRR33591702_1.fastq.gz	Fastqsanger.gz

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Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation

Project description:BCOR (BCL-6 corepressor) is a component of variant Polycomb Repressive Complex 1.1 (vPRC1.1), one of several vPRC1 complexes that catalyze histone H2A ubiquitination thought to play an important role in PRC2 binding and the deposition of H3K27me3 to silence genes. The PCGF Ub-like Fold Discriminator (PUFD) domain at the C-terminus of BCOR forms a heterodimer with PCGF1, serving as a critical interface for its polycomb-dependent functions. Internal tandem duplication (ITD) mutations in BCOR, causing in-frame duplications of 20 to 40 amino acids in the PUFD domain, are observed in heterogenous tumors including sarcomas (kidney, bone and endometrium) and neuroepithelial tumors in the brain. To dissect the molecular mechanisms underlying aberrant function of BCOR-ITD mutants, we employed mouse embryonic stem (mES) cells expressing either transgenic or endogenous BCOR-ITD. Our results indicate that the BCOR-ITD mutation does not disrupt the BCOR-PCGF1 interaction, instead maintaining the integrity of the vPRC1.1 complex. While displaying subtle changes in imprinted gene expression during differentiation toward a neural lineage, BCOR-ITD mutants also had no growth phenotype in culture. Furthermore, we found that CD24+ cells were enriched, as expected, during neural progenitor differentiation in both wildtype and mutant cells. However, sensitization of BCOR-ITD mES cells with EZH2 inhibitor during differentiation resulted in an unexpected enrichment of a CD24+CD26+ subpopulation, indicating aberrant cell fate that was also prevalent in a BCOR truncation mutant. Together, our results suggest that BCOR-ITD may largely retain wildtype function, but with increased susceptibility to synergistic stress on the Polycomb pathway.

2025-05-20 | GSE297344 | GEO

Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation

Project description:To identify vPRC1.1 protein interactions in the context of a mutant BCOR-ITD subunit, we performed cross-linking followed by two-step affinity purification of BioTAP-tagged wildtype BCOR (BCOR-WT) or BCOR-ITD mutant protein in mES cells

2025-06-28 | PXD064792 | Pride

Paediatric BCOR-associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15.

Project description:Clear cell sarcoma of the kidney (CCSK) and primitive myxoid mesenchymal tumour of infancy (PMMTI) are paediatric sarcomas that most commonly harbour internal tandem duplications (ITDs) of exon 15 of the BCOR gene, in the range of 87-114 base pairs (bp). Some cases, instead, have BCOR-CCNB3 or YWHAE-NUTM2 gene fusions. About 10% of cases lack any of these genetic alterations when tested by standard methods. Two cases of CCSK and one PMMTI lacking the aforementioned mutations were analysed using Archer FusionPlex technology. Two related BCOR exon 15 RNA transcripts with ITDs of lengths 388 and 96 bp were detected in each case; only the 388 bp transcript was identified when genomic DNA was sequenced. In silico analysis of this transcript revealed acceptor and donor splice sites indicating that, at the RNA level, the 388-bp transcript was likely spliced to form the 96-bp transcript. The results were confirmed by Sanger sequencing using primers targeting the ITD breakpoint. This novel and unusually long ITD segment is difficult to identify by DNA sequencing using typical primer design strategies flanking entire duplicated segments because it exceeds the typical read lengths of most sequencing platforms as well as the usual fragment lengths obtained from formalin-fixed paraffin-embedded material. As diagnosis of CCSK and PMMTI may be challenging by morphology and immunohistochemistry alone, it is important to identify mutations in these cases. Knowledge of this novel BCOR ITD is important in relation to primer design for detection by sequencing, and using RNA versus DNA for sequencing.

| S-EPMC9353662 | biostudies-literature

UBTF tandem duplication AMLs are sensitive to menin inhibition

Project description:UBTF tandem duplication AMLs are sensitive to menin inhibition

| PRJNA978037 | ENA

Transcription profiling by array of human cytogenetically normal acute myeloid leukemia patient samples with FLT3 internal tandem duplications

Project description:Oligonucleotide expression microarray data used for expression signature associated with FLT3 internal tandem duplications(FLT3-ITD) in samples from older patients with cytogenetically normal AML

2010-07-23 | E-TABM-1029 | biostudies-arrayexpress

BCOR-CCNB3 fusion and BCOR internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.

Project description:Undifferentiated round cell sarcomas (URCSs) usually remained unclassified due to lack of known genetic abnormalities. Herein, we retrospectively collected 5 cases of URCSs and sought to investigate their unique clinicopathologic and molecular features for providing more accurate classification. There were 2 males and 3 females with age ranged from 7 months to 17 years. The tumors were respectively located in the sacrum, fibula, neck, perineum or groin. Microscopically, all 5 tumors were composed of small-to-medium sized cells with primitive morphology and variable cellularity, distributed within loose myxoid or collagenized fibroid stroma. These tumors lacked specific immunophenotypes and known gene rearrangements. However, the expression levels of CD99 and cyclin D1 were variable. RNA-sequencing data identified one BCOR-CCNB3 gene fusion-positive sarcoma occurring in the sacrum of a 17-year-old male patient. Whole genome sequencing analysis detected BCOR exon 15-internal tandem duplication (BCOR-ITD) in the tumor arising in the groin of one 7-month-old female infant. No specific gene abnormalities were found in the other 3 cases. Interestingly, a morphological and immunohistochemical overlap existed between BCOR-rearrangement tumor and BCOR-ITD-positive tumor, including areas with hypercellularity alternating with hypocellularity, a mixture of round cells and focal spindle cells, pale nuclear chromatin, inconspicuous nucleoli and abundant myxoid matrix, diffuse strong cyclin D1 expression, relatively strong expression of CD99 but lower than that in Ewing sarcoma, and a low Ki-67 proliferation index of about 10%. Our findings demonstrated a significant link between genetic aberration and histopathologic appearances, thus supporting the crucial role of genetic characteristics in accurate clinicopathological classification.

| S-EPMC6789234 | biostudies-literature

The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of "CNS tumors with BCOR internal tandem duplication".

Project description: Not available

| S-EPMC7607816 | biostudies-literature

GATA2 deficiency phenotype associated with tandem duplication of the GATA2 locus linked to a common structural variant

Project description:Typical features of GATA2 deficiency were observed in a individual with wild-type GATA2 sequence. The patient had a de novo tandem duplication of 187Kb spanning GATA2 and RPN1 containing a deletion of 25Kb 5’ of RPN1, inherited from the mother. The deletion is a copy number variant present in about 4% of Europeans (GRCh37: esv2725896 and nsv513733; GRCh38: esv3597711) and removes an alternative 5’ start site of RPN1 at 128,400Kb, associated with CTCF and H3K27ac binding peaks. A second copy of GATA2 is translocated to this region by the tandem duplication. RNA-Seq was underatken in order to identify any gene fussion events resulting from the mutation and to inverstigate differences in gene expression between the patient and controls.

2021-05-10 | GSE166201 | GEO

BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets.

Project description:Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

| S-EPMC8070097 | biostudies-literature

UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

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