Expression data from AZA treated megakaryocytic cells under TPO-RA stimulation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144410 | GEO | 2022/08/25
REPOSITORIES: GEO
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Project description:Methylation data for MDS bone marrow derived MSCs before and after 5-Azacitidine treatment. Methylation profiles were measured using the Infinium Human MethylationEPIC BeadChip (Illumina). There are 5 healthy MSC and 8 high-risk MDS-MSC samples, untreated and treated with 5-Azacitidine in vitro.
2019-09-06 | GSE119617 | GEO
Project description:<p>This single-arm study design has been selected to investigate the safety of combination therapy with Vidaza® (azacitidine) and Revlimid® (lenalidomide) in a population of 18 participants with advanced MDS for the Phase I portion, and 18 participants for the Phase II portion. The multi-center nature of the study should enhance the general applicability of the results. Participants with advanced MDS were chosen because it is expected that the combination of the two drugs will by myelosuppressive, which can be considered a necessary toxicity to effect improvements in PR and CR rates in this advanced population, akin to participants with AML. Finally, the combination was chosen to be studied because currently available therapies in this population, and their effectiveness, are limited, and single-agent Vidaza® (azacitidine), while effective at delaying transformation to AML or death, is not curative.</p> <p>The doses of Revlimid® (lenalidomide) in this study are similar to those that were demonstrated to have an effect and to be well-tolerated in participants with MDS. Doses for Vidaza® (azacitidine) are similar to those used in the pivotal trial, though for a 5-day treatment period instead of 7 to minimize toxicity for the first 3 blocks of participants, and then at a lower dose over a protracted period of time to explore the safety of a 10-day treatment course.</p>
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Project description:This study includes 2 cohorts of samples. First cohort consists out of BM aspirates from 4 healthy individuals and 12 patients diagnosed with AML, MDS or CMML. Second cohort includes 5 healthy individuals and 17 patients diagnosed with AML, MDS or CMML. MDS and CMML patients were treated with 5-AZA on 6 cycles and samples were obtained before the treatment and 15 days after 1 and 6 rounds of treatment.
2019-12-10 | E-MTAB-8208 | biostudies-arrayexpress
Project description:A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development.
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Project description:The nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.
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Project description:NKL homeobox genes encode transcription factors which impact normal development and hematopoietic malignancies if deregulated. Recently, we established a NKL-code which describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL-genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6 and SOX7. SiRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1 and SIX5, and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte-erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating megakaryocytic and erythroid differentiation processes, and thereby driving formation specific AML subtypes.
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2013-11-21 | E-GEOD-48153 | biostudies-arrayexpress
Project description:Cytopenia in at least one of the hematopoietic lineages (RBCs, WBCs or platelets) is a hallmark feature of MDS, indicating the lack of ability to support HSPC proliferation and the retention of their multilineage potential in the bone marrow. Here, wel investigate MDS-MSCs (with and without 5-azacitidine pre-treatment) as feeder layers for healthy CD34+ HSPCs. We performed RNA sequencing of co-cultured CD34+ HSPCs to compare their transcriptomic signatures after exposure to treated vs untreated MDS-MSCs.
2019-09-30 | GSE119916 | GEO
Project description:In a two-stage study we investigated levels of Immunoglobulin G (IgG) reactivity in plasma from Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) post MDS patients (59 and 16 cases respectively) as compared to healthy cohort (34). In Stage I we utilized high-throughput protein arrays (23 232 total signals, in duplicate) to identify proteins of high-interest. In Stage II we designed new protein arrays (352 total signals, in duplicate) to further focus on 25 of the proteins from Stage I and expanded to a larger cohort, including both male and female samples (161 MDS and 43 AML patients; 112 healthy controls). Stage I resulted in 35 proteins displaying increased IgG reactivity in patients as compared to the healthy controls (P< 4.3 x10-07, Bonferroni Corrected P<0.01). This protein subset included 14 proteins associated with cancer, 12 with apoptosis, and 3 with the NFAT Regulation canonical pathway. Using the focused arrays we performed a classification of MDS patients and healthy controls. Stage II subsequently identified a high-interest focused set of 3 proteins, namely AKT3, FCGR3A and ARL8B displaying aberrant increased reactivity in patient subgroups, in concordance with Stage I. Autoantibody reactivity against specific proteins provides complementary information to other known molecular signatures for MDS and may enhance our capabilities for detecting and classifying MDS. In the study presented here, MDS patients were classified into Stable, Transforming or AML post MDS (L) classes retrospectively. The different patients were compared to a healthy cohort to assess increased autoantibody reactivity to specific patients as opposed to healthy groups Stage 2 of study: 633 Files analyzed for: 316 Patients in duplicate and a negative control. The proteins on the array were selected following a first stage using ProtoArrays
2013-11-21 | E-GEOD-48154 | biostudies-arrayexpress