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

ABSTRACT: 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

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Embryonic Stem Cell

DISEASE(S): Brain Cancer

SUBMITTER: Zuzer Dhoondia

LAB HEAD: MITZI I KURODA

PROVIDER: PXD064792 | Pride | 2025-06-28

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	651002_r1_BCOR_A_ITD_INPUT.mzid	Mzid
	651003_r1_BCOR_A_ITD_IP.mzid	Mzid
	651004_r1_BCOR_A_WT_INPUT.mzid	Mzid
	651005_r1_BCOR_A_WT_IP.mzid	Mzid
	651006_r1_BCOR_C_ITD_INPUT.mzid	Mzid

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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

MicroRNA profiling by array of older patients with cytogenetically normal AML with or without FLT3 internal tandem duplications

Project description:microRNA expression microarray data used for expression signature associated with FLT3-ITD in samples from older patients with cytogenetically normal AML

2010-07-22 | E-TABM-1032 | biostudies-arrayexpress

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

ScanITD: Detecting internal tandem duplication with robust variant allele frequency estimation.

Project description:Internal tandem duplications (ITDs) are tandem duplications within coding exons and are important prognostic markers and drug targets for acute myeloid leukemia (AML). Next-generation sequencing has enabled the discovery of ITD at single-nucleotide resolution. ITD allele frequency is used in the risk stratification of patients with AML; higher ITD allele frequency is associated with poorer clinical outcomes. However, the ITD allele frequency data are often unavailable to treating physicians and the detection of ITDs with accurate variant allele frequency (VAF) estimation remains challenging for short-read sequencing. Here we present the ScanITD approach, which performs a stepwise seed-and-realignment procedure for ITD detection with accurate VAF prediction. The evaluations on simulated and real data demonstrate that ScanITD outperforms 3 state-of-the-art ITD detectors, especially for VAF estimation. Importantly, ScanITD yields better accuracy than general-purpose structural variation callers for predicting ITD size range duplications. ScanITD enables the accurate identification of ITDs with robust VAF estimation. ScanITD is written in Python and is open-source software that is freely accessible at https://github.com/ylab-hi/ScanITD.

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Expanding the clinical phenotype of <i>FGFR1</i> internal tandem duplication.

Project description:Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. This ITD variant is somatic mosaic in nature as supported by a diminished variant allele frequency in the lesional tissue and by its absence in peripheral blood. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare, and this report broadens the phenotypic spectrum of somatic mosaic FGFR1-related disease.

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UBTF tandem duplication defines High-risk Pediatric Acute Myeloid Leukemia

Project description:Genomic profiling of relapsed pediatric AML demonstrated an increase in KMT2A and NUP98 rearrangements when compared to de novo pediatric AML, as well as an increase in WT1 mutations. Notably, we identified recurrent (9% of relapse cohort) exon 13 duplications in UBTF in pediatric AML cases that previously lacked known driver alterations. These UBTF-tandem duplication (TD) pediatric AMLs occur in approximately 4% of all pediatric AMLs and are less common in adult AMLs, are associated with normal karyotype or trisomy 8 cytogenetic abnormalities, co-occur with WT1 and FLT3-ITD, have an expression profile similar to NUP98-NSD1 and NPM1 mutant AMLs and are independently associated with poor outcome.

| EGAS00001005760 | EGA

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

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

| PRJNA1263563 | ENA

Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia.

Project description:FLT3 internal tandem duplications (FLT3/ITDs) in the juxtamembrane domain are found in approximately 25% of acute myeloid leukemia (AML) patients, ranging in size from 3 to hundreds of nucleotides. We examined whether the sizes of FLT3/ITDs were associated with clinical outcomes in 151 AML patients enrolled in Southwest Oncology Group studies: S9333 and S9500. FLT3/ITDs were identified in 32% of patients (median ITD size = 39 nucleotides; range, 15-153 nucleotides). The CR rates were 35%, 67%, and 52% for patients with large (>or= 40), small (< 40), and no ITDs, respectively (P = .19). Increasing ITD size was associated with decreasing OS (estimated 5-year OS: large = 13%, small = 26%, and no ITD = 21%, P = .072) and RFS (estimated 5-year RFS: large = 13%, small = 27%, and no ITD = 34%, P = .017). These studies suggest that ITD size may have prognostic significance.

| S-EPMC1895777 | biostudies-literature

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis.

Project description:Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex-related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3-ITD) mutation and co-mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML-TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex-associated molecular differences. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia-associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3-ITD-mutated AML. Thus, we suggest optimization of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex-specific considerations.

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Diagnostic features in paediatric MDS-EB with UBTF-internal tandem duplication: defining a unique subgroup.

Project description:AimTandem-duplications of the UBTF gene (UBTF-TDs) have recently been identified as a new genetic driver in young individuals with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Disease in these newly defined subgroups is characterized by poor response to standard intensive chemotherapy and inferior survival of the affected patients. However, a thorough analysis of bone marrow histomorphology of UBTF-mutated neoplasia has not been undertaken thus far.Methods and resultsIn this retrospective study, we investigated the characteristic histopathological features of a cohort comprising 14 paediatric MDS patients with an excess of blasts (MDS-EB) and UBTF-TD. Bone marrow biopsies from these patients revealed hypercellularity and severe dysplasia across all three haematopoietic lineages. In particular, a marked hyperplastic megakaryopoiesis characterized by the presence of frequent micromegakaryocytes and a high number of monolobulated cells forming small clusters was observed. Additionally, erythropoiesis was left-shifted, with numerous blastoid precursors. The granulopoietic precursors displayed prominent UBTF-positive nucleoli.ConclusionThe unique combination of these histomorphological features strongly suggests a possible UBTF aberration. It will allow initiating the appropriate genetic testing to confirm the presence of UBTF-TD and identify potential additional genetic alterations. Such molecular profiling will not only contribute to a better understanding of the disease mechanism, but also facilitate more rational treatment approaches for these high-risk paediatric MDS patients.

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