Similar Datasets
Project description:Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, resulting in dismal prognosis. The most recent World Health Organization classification recognizes myeloid neoplasms with MECOM rearrangement as acute myeloid leukemia (AML) with defining genetic abnormalities. To date, patient-derived induced pluripotent stem cell (iPSC) models have helped elucidate the pathogenic processes of human diseases and serve as a valuable platform for drug discovery. However, their utility in cancer biology remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harboring t(3;8)(q26.2;q24) and differentiated them into hematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in MECOM promoter/enhancer and MYC blood enhancer cluster (BENC). Notably, MDS-iPSCs exhibited H3K27ac activation at the MECOM promoter, even in the pluripotent state, with higher MECOM expression than control iPSCs, indicating that the aberrant histone acetylation of MDS cells could not be completely reset after reprogramming. Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor JQ1 on iPSC-derived MDS cells by suppressing activated MECOM, suggesting BET inhibitors as potential novel therapeutic drugs for MDS/AML carrying t(3;8)(q26.2;q24). Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.
2025-01-22 | GSE248239 | GEO
Project description:Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematologic malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.
2025-01-22 | GSE248238 | GEO
Project description:Modeling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs
| PRJNA1043073 | ENA
Project description:Modeling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs [ChIP-seq]
| PRJNA1043079 | ENA
Project description:Modeling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs [RNA-seq]
| PRJNA1043080 | ENA
Project description:Data in this article presents the results of conventional cytogenetics and fluorescence in situ hybridization (FISH) analyses in 129 patients with confirmed MECOM rearrangement (https://doi.org/10.1016/j.cancergen.2019.03.002) [1]. Generally, the MECOM rearrangement has arisen through translocation, inversion, and insertion and/or unknown mechanism. In addition to the typical chromosomal aberrations, inv(3)(q21q26.2) and t(3; 3)(q21; q26.6) [2-4], over 50% of cases presented here exhibit a wide spectrum of MECOM rearrangement-driven, atypical chromosomal aberrations, including inv(3) with breakpoint other than 3q21; t(1; 3); t(2; 3); t(3; 6); t(3; 8); t(3; 12); t(3; 17); t(3; 21) as well as an insertion of 3q26.2 into different chromosomes. These cases are thoroughly characterized by karyotyping, interphase-, metaphase-, map-back FISH and whole chromosomal painting (WCP) analyses.
| S-EPMC6545385 | biostudies-literature
Project description:To elucidate the transcriptional and epigenetic alterations underlying the neurogenic defects of FA-NSCs, we conducted gene expression microarray analysis and global DNA methylation profiling. The gene expression pattern of gene-corrected NSCs (C-FA-NSCs) resembled that of control-NSCs but clustered distantly from FA-NSCs (Fig. 6F and Table S1). Hierarchical clustering based on DNA methylation levels in the promoter region (+/-1.5kb from TSS) of genes whose expression levels were rescued in C-FA-NSCs, placed C-FA-NSCs closer to control-NSCs and away from FA-NSCs (Fig. 6G), although this pattern was not seen at the whole genome level (Fig. S4C). This suggests that FANCA gene correction leads to specific methylation changes in a subset of promoters. Examination of the methylomes of NSCs derived from Fanconi Anemia iPSCs before and after gene correction by targeted bisulfite sequencing with padlock probes
2014-05-15 | E-GEOD-57685 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-05-21 | E-GEOD-57828 | biostudies-arrayexpress
Project description:Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.
| S-EPMC4940830 | biostudies-literature
Project description:Fibroblastic/myofibroblastic neoplasms represent a broad, and occasionally diagnostically challenging, category of soft tissue neoplasms. A subset of these tumors defy conventional classification. However, with the advent of next-generation sequencing, the identification of disease-defining molecular alterations is gradually improving their subclassification. Following identification of two index cases of a distinctive fibroblastic neoplasm with a fusion gene involving PRRX1 and NCOA1, we performed a retrospective review to further characterize this entity. We identified two additional cases, including one with a fusion between PRRX1 and NCOA2. The average patient age was 38?years, and three patients were female. Two tumors occurred on the neck, and the others involved the groin and thigh. Tumors were centered in the subcutis and ranged from 2.3 to 14.0 cm (average 5.8 cm). Morphologically, they were predominantly hypocellular, with focal hypercellularity. They were composed of monomorphic spindle-stellate cells with a vague fascicular pattern. The nuclei were bland with only rare mitotic activity, and occasional multinucleation. The intervening stroma was typically abundant and ranged from myxoid to collagenous, with frequent rope-like collagen bundles. Three of the cases had a prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn-like vessels. Immunohistochemistry was negative for desmin, smooth muscle actin, S100, CD34, keratin, and epithelial membrane antigen. Each of the patients was treated by simple excision and none of the tumors were associated with local recurrence or metastasis. Based on their unique morphological and molecular attributes, we believe this represents a novel fibroblastic tumor for which we have tentatively proposed the name "PRRX-NCOAx-rearranged fibroblastic tumor."
| S-EPMC7104602 | biostudies-literature