Oncogenic ZEB2 activation drives sensitivity towards LSD1 inhibition in T-cell acute lymphoblastic leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA324824 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3647940.fastq.gz | Fastqsanger.gz | |||
| SRR3647960.fastq.gz | Fastqsanger.gz | |||
| SRR3647970.fastq.gz | Fastqsanger.gz | |||
| SRR3647941.fastq.gz | Fastqsanger.gz | |||
| SRR3647961.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2017-02-03 | GSE83128 | GEO
Project description:We screened for the changes in gene expression induced by an LSD1 inhibitor to elucidate the mechanism of its cytotoxic effect on T-cell acute lymphoblastic leukemia (T-ALL).
2017-08-15 | GSE85956 | GEO
Project description:RNA sequencing was performed on biological triplicates of p53 null T-ALL cells with ZEB2 overexpression (P53/R26-Zeb2tg/tg) versus p53 null T-ALL cells without Zeb2 overexpression (P53/R26+/+) treated with 100nM GSK2879552 for 24h versus their corresponding DMSO treatment controls. P53/R26+/+ and P53/R26-Zeb2tg/tg tumor lines displayed a very distinct gene expression signature under baseline (DMSO) conditions in line with our previous observations that Zeb2 driven thymomas reflect a more immature T-ALL subtype. GSK2879552 is a potent, selective and orally bioavailable inhibitor of the lysine-specific histone demethylase 1 (LSD1). LSD1i treatment in control P53/R26+/+ cell lines only caused limited effects on overall transcription. In contrast, gene transcription was more severely affected by LSD1 perturbations in the P53/R26-Zeb2tg/tg lines with significant changes in the expression transcripts enriched for signalling pathways essential for embryonic development (like TGFbeta and Wnt signalling), genes involved in transcriptional repression/regulation, apoptosis and DNA replication/repair. All together, these results demonstrate that Zeb2 overexpression modulates murine T-ALL responsiveness to LSD1 inhibitors.
2017-02-03 | GSE83127 | GEO
Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
2021-03-23 | PXD022212 | Pride
Project description:Study of loss of ZEB2 in breast cancer cells in vitro and in vivo: gene expression and phenotypic switch to more benign behavior of the cancer cells. Morphological, functional and gene microarray analysis following ZEB2 knockdown in MDAMB231 cells reveals gain of epithelial differentiation, reduction of migration, invasion and metastatic capability. The measurement of ZEB2 transcriptional activity in tumor cells efficiently predicts the probability of breast cancer patient survival. Global gene expression profiles were measured using Affymetrix U133 plus2 microarrays in MDAMB231 cells (control and ZEB2 shRNA and siRNA knockdown cells on plastic)
2016-03-15 | E-GEOD-27966 | biostudies-arrayexpress
Project description:Genomics of drug sensitivity in acute lymphoblastic leukemia
| EGAS00001006336 | EGA
Project description:Previous studies have established that the cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity. However, the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to cytotoxic chemotherapy and express high levels of the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared drug sensitivity and expression profiles of murine and human leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein stability and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 inhibitors in addition to classical genotoxic stresses. p53 loss-of-function in Evi1low progenitor-derived leukemias induces resistance to LSD1 inhibition. By contrast, Evi1high leukemias are sensitized to LSD1 inhibition by the BH3 mimetic venetoclax, resulting in enhanced apoptosis and greater reductions in disease burden. Our findings demonstrate a cell-of-origin determined novel role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in high-risk, chemoresistant EVI1high AML.
2020-07-29 | GSE153025 | GEO
Project description:The multi-domain transcription factor ZEB2 controls embryonic and adult cell fate decisions and maturation in many stem/progenitor cell types. Defects in these processes in specific cell types underlie Mowat-Wilson syndrome (MOWS), which is caused by ZEB2 haplo-insufficiency. Human ZEB2, like mouse Zeb2, is located on chromosome 2 downstream of an approximately 3.5 Mb-long gene-desert, lacking any protein-coding gene sequence. Using temporal high-resolution Targeted Chromatin Capture (T2C), we show major chromatin structural changes based on mapping in-cis proximities between the ZEB2 gene promoter and this gene desert during neural differentiation of induced pluripotent cells (iPSCs), including at early neuroprogenitor cell (NPC)/rosette state, where ZEB2 mRNA levels increase significantly. Combining T2C with histone-3 acetylation mapping, we identified three novel candidate enhancers about 500 kb upstream of the ZEB2 transcription start site (TSS). Functional luciferase-based assays in heterologous cells and NPCs reveal co-operation between these three enhancers. This study is the first to document in-cis regulatory elements (REs) located in ZEB2’s gene desert. The results further show the usability of T2C for future studies of ZEB2 REs in differentiation and maturation of relevant cell types, and the molecular characterization of identified MOWS patients that lack mutations in ZEB2 protein-coding exons.
2020-08-03 | GSE147000 | GEO
Project description:Plasmacytoid dendritic cells (pDCs) develop from pre-pDCs, while two lineages of conventional DCs (cDC1s and cDC2s) develop from lineage-committed pre-cDCs. A number of transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2, Id2) and cDC1s (IRF8, Id2 and Batf3) however, those required for the early commitment of pre-cDCs towards the cDC2 lineage are unknown. Here we identified the TF Zinc finger E box binding homeobox 2 (Zeb2), to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onwards, and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c+ cells had a cell intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c+ cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was upregulated in cDC2s and pDCs from conditional knock-out mice. Zeb2 ChIP analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2.
2016-05-01 | GSE79903 | GEO
Project description:T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during infection. We find that at high concentrations T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential. Splenocyte derived CD8+ T cells from C57BL/6 mice with either a wildtype (WT) (GzmB-Cre Zeb2+/+) or GzmB-Cre Zeb2-fl/fl (Zeb2-/-) backgrounds, following 8 days post infection with LCMV-Armstrong, were subsetted into KLRG1-hi/IL-7R-lo populations (terminal effectors, TE) or KLRG1-lo/IL-7R-hi (memory precursors, MP) populations. Four experimental groups, each with 3 samples, comprised of TE+WT, MP+WT, TE+ZEB2-/-, and MP+ZEB2-/-, were profiled for gene expression utilizing a polyA RNA prep and hybridized to the Illumina microarray platform IlluminaWG-v2.0.
2015-09-15 | E-GEOD-72408 | biostudies-arrayexpress