Lineage-Specific TOP2A Cleavage Landscape in Leukemia Cell
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA412503 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Topoisomerases II (TOP2) play role in relief of torsional stress during DNA replication and gene transcription, and TOP2 is also a target of anticancer agents which cause secondary leukemia. To address cell lineage-specific TOP2A cleavage relative to leukemia, here we profile genome-wide TOP2A cleavage in human acute lymphoblastic leukemia (ALL) cell line CEM, and compare to TOP2A cleavage landscape of chronic myelogenous leukemia (CML) cell line K562. We find that TOP2A cleavage activity are correlated with chromosome length, suggesting that TOP2A cleavage is critical for segregation or supercoil relaxation of long chromosomes. Meanwhile, we find that evolutionally conserved TOP2A cleavage cluster regions (CCRs) are depleted in gene promoter and enriched in introns and 3’ UTR, and TOP2A cleavage genes tend to be highly expressed, indicating the conserved function of TOP2A cleavage in promoting transcription elongation and activation. In addition, we found that the oncogenic transcription factor complex TAL1, GATA3 and RUNX1 can further promote the activation of TOP2A cleavage genes by binding to their promoters. Further analysis reveal that native TOP2A cleavage are lineage-specific, which play role in cell commitment and leukemia development , while drug-enhanced TOP2A cleavage promote apoptosis of cancer cells in both ALL and CML.Taken together, our findings suggest that native TOP2A cleavage function in long chromosome segregation and transcription activation, and together with the transcriptional regulatory factors shape the commitment of leukemia cell.
2023-12-31 | GSE104384 | GEO
Project description:Type II topoisomerases orchestrate proper DNA topology and they also are the targets of anticancer drugs that cause leukemias with balanced translocations as secondary cancers. Here, we develop a novel high-throughput sequencing technology to define TOP2 cleavage sites at single base precision in human cells and use the technology to characterize TOP2A cleavage genome-wide in the K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence predilections, occurs in cleavage cluster regions (CCRs) and is enriched in introns and lincRNA loci. In coding genes we discover a bias of TOP2A CCRs towards the distal regions of gene bodies and proximal shifts in TOP2A CCRs with TOP2 poisons. We find high TOP2A cleavage levels in the genes involved in translocations associated with TOP2 poisons in leukemia. In addition, we find that large a proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. By making comparisons to ENCODE data, we uncover distinct TOP2A CCR clusters that overlap with marks of gene transcription, open chromatin and enhancers. Our findings implicate TOP2A as the DNA damage mediator in oncogenic translocations more broadly than was previously appreciated. They also identify TOP2A as a functional DNA element that contributes to the regulation of transcription elongation and gene activation.
2017-03-08 | GSE79593 | 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:This SuperSeries is composed of the following subset Series: GSE40684: Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [ChIP-Seq] GSE40685: Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [Expression] Refer to individual Series
2012-09-28 | E-GEOD-40686 | biostudies-arrayexpress
Project description:Human infants exhibit innate social behaviors at birth, yet little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused behavioral defects related to core symptoms of autism, including impairments in social interaction and communication. Mutation of Top2a in zebrafish caused downregulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets possess binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation. Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.
2021-09-20 | GSE181730 | GEO
Project description:Landscape of TOP2A-mediated DNA cleavage across the human genome
| PRJNA316335 | ENA
Project description:Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL-chimeras that drive pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase, taspase1, however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of full-length MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version and this stabilization of the uncleaved MLL1 can result in the displacement of MLL-chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL-chimeras from chromatin. Furthermore, inhibition of CKII in MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive MLL leukemia.
2019-01-02 | GSE90762 | GEO
Project description:Malignant nerve sheath tumors (MPNST) are rare types of malignant soft tissue sarcomas and characterized by high resistance for current chemotherapeutic strategies, including topoisomerase 2a (TOP2A) inhibitor, etoposide. Although the poor therapeutic or severe side effects of etoposide in MPNST patients are demonstrated, novel molecular targets that promote tumor malignancy have not been identified. Previously, we reported that paired related-homeobox 1 (PRRX1) serves as a malignant factor in human osteosarcoma. Here, we found that expression level of PRRX1 in tumor tissues, especially sarcomas, are higher than in normal tissues using database analysis. PRRX1 was expressed in various human sarcoma tissues, and its level increased during malignant progression from schwannoma or neurofibroma to MPNST. High expression of PRRX1 was also associated with poor prognosis of human MPNST patients, and PRRX1 knockdown suppressed proliferation, invasion and tumorigenic potential of human MPNST cell line, HS-PSS. Immunoprecipitation and mass spectrometry analysis revealed that PRRX1 interacts with TOP2A, and human MPNST patients with high expression of TOP2A showed poor prognosis. Interestingly, database analysis revealed that expression level of TOP2A in tumor tissues were positively correlated with PRRX1. TOP2A knockdown in HS-PSS suppressed proliferation, and inhibited the migration induced by PRRX1A overexpression. Overexpression of PRRX1 and TOP2A cooperatively increased migration and expression of tumor-malignancy associated gene sets, including EMT, mTORC1, KRAS and SRC signaling pathways. Inhibition of PRRX1-TOP2A interaction would be a novel tumor-selective therapeutic strategy that has less severe side effects than current chemotherapies.
2023-05-31 | GSE214899 | GEO
Project description:Functional Genomic Landscape of Acute Myeloid Leukemia
| PRJNA484069 | ENA
Project description:Relapsed Acute Lymphoblastic Leukemia (ALL): Mutational Landscape
| PRJNA597498 | ENA