The transcriptional factor ONECUT3 is a driver and therapeutic target for complex karyotype MDS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA837004 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19159406_1.fastq.gz | Fastqsanger.gz | |||
| SRR19159406_2.fastq.gz | Fastqsanger.gz | |||
| SRR19159407_1.fastq.gz | Fastqsanger.gz | |||
| SRR19159407_2.fastq.gz | Fastqsanger.gz | |||
| SRR19159408_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Early, low risk IPSS (International Prognostic Scoring System) myelodysplasia (MDS) is a heterogeneous disorder where the molecular and cellular haematopoietic defects are poorly understood. To gain insight into this condition, we analyzed gene expression profiles of marrow CD34+ progenitor cells from normal karyotype, low blast count MDS patients, age-matched controls and patients with non-MDS anaemia. The aim of the study was to further understanding of the cellular defect in MDS and to identify biomarkers of disease Keywords: Disease v normal
2005-08-05 | GSE2779 | GEO
Project description:Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) harboring both inv(3)/t(3;3) and monosomy 7 (-7) are highly aggressive myeloid cancers whose molecular pathogenesis and therapeutic vulnerability remain elusive. High throughput drug screens, CUT&Tag/RNA sequence and functional assays using human MDS/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS/AML with inv(3)/t(3;3) and -7 through activation of GADD45γ-p38-p53 axis. EVI1 activated in 3q-rearranged MDS/AML was responsible for GADD45γ silencing by direct binding to its consensus sequence within GADD45γ promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS/AML with inv(3)/t(3;3) and -7 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS/AML cells with inv(3)/t(3;3) and -7 possess apoptosis evasion mechanism through EVI1-PRC2-mediated repression of GADD45γ-p38-p53 axis, which is a potential therapeutic vulnerability in MDS/AML patients with these high-risk cytogenetic lesions.
2024-06-29 | GSE270760 | GEO
Project description:IGF2 is an epi-driver and therapeutic target in hepatocellular carcinoma
| PRJNA338010 | ENA
Project description:Early, low risk IPSS (International Prognostic Scoring System) myelodysplasia (MDS) is a heterogeneous disorder where the molecular and cellular haematopoietic defects are poorly understood. To gain insight into this condition, we analyzed gene expression profiles of marrow CD34+ progenitor cells from normal karyotype, low blast count MDS patients, age-matched controls and patients with non-MDS anaemia. The aim of the study was to further understanding of the cellular defect in MDS and to identify biomarkers of disease Experiment Overall Design: Bone marrow (BM) CD34 cells were purified from patients with MDS, non-MDS anemia and from normal donors. Total RNA was extracted from Tri-reagent and quality verified on by capillary electrophoresis (Agilent). RNA was amplified by the Affymetrix small sample protocol. cRNA was hybridised to Affymetrix U133A chips under standard conditions. Initial data was analysed in MAS 5.0
2007-09-20 | E-GEOD-2779 | biostudies-arrayexpress
Project description:This study describes a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is the first description of a recurrent telomere fusion event in myeloid malignancy. The derivative chromosome is further characterised by the presence of nucleolus organiser region material from the chromosome 22 short arm, loss of the putative tumour suppressor gene at 20q12 and secondary rearrangements including gain or amplification of 20q material adjacent to the deletion encompassing 20q12. The presence of residual telomere sequence at the site of translocation in three of the four cases is compelling support for telomere fusion, and supports previous evidence that over half of dicentric chromosomes involving 20q are produced by telomere fusion events. We propose that the sequence of events producing this chromosome abnormality is initial formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, followed by breakage-fusion-bridge cycles causing 20q12 deletion and 20q11.2 gain which provide a growth advantage to the cell. Selection of these clones contributes to leukaemogenesis. Finding recurrent patterns in the complex genome reorganisation events which characterise poor prognosis, complex karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies. The sample consists of leukaemia specimens from three different cases of AML and MDS. The consistent feature was the presence of a dicentric chromosome formed from chromosomes 20 and 22.
2016-06-30 | E-GEOD-64050 | biostudies-arrayexpress
Project description:About 40% of patients with myelodysplastic syndromes (MDS) present with a normal karyotype and they are facing different courses of disease. To advance the biological understanding and find molecular prognostic markers we performed a high resolution oligonucleotide array study of 107 MDS patients (FAB) with a normal karyotype. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 had an additional 5q31.2 deletion of the AML/MDS region; the smallest deletion identified so far and includes the putative tumor suppressor (ts) genes EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total 42/107 (39%) cases had genomic imbalances, deletions were more frequent than gains. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS but points to interesting genes which may have diagnostic and prognostic impact. Array CGH experiment, MDS tumor cells vs. control DNA. Total of 107 tumors.
2011-01-30 | E-GEOD-24602 | biostudies-arrayexpress
Project description:Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by ineffective hematopoiesis and high propensity to leukemias. Although a number of gene targets have been identified, in many MDS cases, particular genetic targets are unknown. In this study, we performed genome-wide profiling of copy number (CN) abnormalities and allelic imbalances in MDS genomes in order to clarify the distribution of LOH (loss of heterozygosity) and identify their target genes. We analyzed a total of 171MDS and MDS/MPD specimens, including 7 RA/RARS, 23 RCMD/RCMD-RS, 6 5q-syndrome, 30 RAEB-1, 40 RAEB-2, 4 therapy related-MDS/AML, 5 MDSu, 17 CMML-1, 16 CMML-2, 24 overt AML, using high-density SNP arrays. The data were analyzed by CNAG/AsCNAR software we specifically developed for allele-specific CN analysis and sensitive LOH detection. MDS showed characteristic CN profiles in SNP array analysis. Of particular interest is the finding of high frequency of CN-neutral LOH (Uniparental disomy,UPD), which were observed in 51 of 171 (30%) MDS cases. They preferentially involved 1p, 1q, 4q, 7q, 11q, 17p and other chromosomal segments, which were associated with homozygous mutations of both loss-of-function mutations and gain-of function mutations of tumor suppressor genes and cellular oncogenes, including TP53 (17p UPD), AML1/RUNX1 (21q UPD), Nras and cMPL (1p UPD), JAK-2 (9p UPD), and FLT3 (13q UPD). Next we tried to identify a new gene target in 11q UPD, which was most common UPD region in this study and many of these cases were CMML with a normal karyotype. The minimum 11q UPD segment is about 2Mb which existed in 11q23. We sequenced coding exons of c-cbl and detected homozygous mutations in 8 of 9 MDS cases with 11q UPD (CMML= 5, RAEB= 3, overt leukemia= 1), but very rare in cases without 11q UPD (1/162), demonstrating that the mutation is tightly linked to 11q UPD. These mutations were 8 point mutations and 1 micro-deletion, they were accumulated in the linker or RING domain. These c-cbl mutants can transform NIH3T3 in a dominant manner and these mutants are phosphorylated and activate PI3K-Akt pathway. To investigate the functions of these mutants in hematopoietic cells, we introduced these mutants into c-kit(+)Sca1(+)Lin(-) murine bone marrow cells, it prolonged replating capacity of these hematopoietic progenitors. Keywords: SNP-chip To identify oncogenic lesions in MDS, we performed a genome-wide analysis of primary MDS samples using high-density SNP arrays (Affymetrix GeneChip).
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Project description:FAM83H-AS1 is a non-coding oncogenic driver and therapeutic target of lung adenocarcinoma
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Project description:MDS is characterized by a disturbed function of the myeloid lineage of the hematopoietic system that may transform to AML, a malignant disease of the myeloid compartment. Epigenetic and genetic aberrations contribute to the initiation and progression of MDS/AML. GFI1 is a transcriptional repressor, which regulates expression of its target genes by, among other approaches, recruiting HDACs to its target genes to remove histone 3 lysine 9 (H3K9) acetylation, a marker for active gene expression. Low levels of GFI1 expression and deletion of one GFI1 allele contribute to MDS/AML development in human patients and are associated with a specific gene expression signature and inferior prognosis. To explore the mechanism behind this, we used a mouse strain, which expresses GFI1 only at 5-10% of the normal level (GFI1-Knock-down (KD)). Knock-down of GFI1 or loss of one murine Gfi1 allele reduced latency and increased incidence of AML in different murine models of human MDS/AML development. On the epigenetic level, KD of Gfi1 lead to increased amount of H3K9 acetylation, resulting in increased expression of genes involved in AML development. On a translational level both murine as well as human AML cells with low expression of GFI1 are resistant to standard epigenetic therapy. We show that treatment with histone acetyltransferase inhibitors might be a novel treatment approach for low Gfi1-expressing blast cells. GFI1 has a dose dependent role in myeloid malignancies and is a biomarker for therapeutic intervention. We used microarrays to detail the global programme of gene expression in bone marrow cells of Nup98HoxD13 leucemic mice and identified distinct classes of up-regulated genes during this process. Bone marrow cells of leukemic mice (from KI & KD Nup98HoxD13 mice) were collected for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain homogeneous populations of leukemic cell population, so we took samples of mice which had the same age.
2016-07-31 | E-GEOD-72489 | biostudies-arrayexpress