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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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			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.

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

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

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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.

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

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