WGS of AML during PARPi therapy
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ABSTRACT:
PROVIDER: EGAS00001002274 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Whole genome sequencing on Illumina X10 machines of up to 100 Adult ALL matched normal-tumour pairs
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Project description:Genome-wide transcription factor binding profiles provide valuable insights into hematopoietic development and malignancies. Today, advanced computational methods exploit cis-regulatory information to predict complex gene regulatory networks controlled by transcription factors. However, these prediction methods still require large amounts of reference data or experimental expertise. Here, we present a low-requirement network-based computational framework that exploits bidirectional transcription marked regulatory elements to identify important transcription factors driving hematopoietic decision making. Using CAGE-seq we predicted TF binding and confirmed experimentally validated TF important in cell conversion strategies by exploiting bidirectional regions. Next, we applied our framework to predict driving transcription factors in induced normal erythropoiesis and early myelopoiesis, as well as in acute myeloid leukemia associated MLL-AF9-driven immortalisation. Our approach allowed the identification of experimentally validated as well as thus far unexplored transcription factors in these processes.
2022-11-09 | GSE204707 | GEO
Project description:PurposeInfections due to severe neutropenia are the most common therapy-associated causes of mortality in patients with acute myeloid leukemia (AML). New strategies to lessen the severity and duration of neutropenia are needed.MethodsCytarabine is commonly used for AML consolidation therapy; we compared high- and intermediate-dose cytarabine administration on days 1, 2, and 3 (AC-123) versus days 1, 3, and 5 (AC-135) in consolidation therapy of AML. Recently, clinical trials demonstrated that high-dose AC-123 resulted in a shortened white blood cell (WBC) recovery time compared with high-dose AC-135. Our main hypothesis is that this is also the case for different cytarabine dosage, granulocyte colony-stimulating factor (G-CSF) administration, and cycle lengths. We analyzed 334 treatment schedules on virtual cohorts of digital twins.ResultsComparison of 32,565 simulated consolidation cycles resulted in a reduction in the WBC recovery time for AC-123 in 99.6% of the considered cycles (median reduction 3.5 days) without an increase in the number of leukemic blasts (lower value in 94.2% of all cycles), compared to AC-135.ConclusionOur numerical study supports the use of AC-123 plus G-CSF as standard conventional AML consolidation therapy to reduce the risk for life-threatening infectious complications.
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Project description:In this study, a cross species hybridization (CSH) approach was used to evaluate whole transcriptome changes during carotenoid accumulation in the storage root of carrot (Daucus carota). Carotenoids are isoprenoid compounds providing red, yellow and orange color to plants. Previous gene expression analyses of carotenoid accumulation in non-model plant species have primarily used a candidate gene approach. Since global transcriptome analyses require extensive genome sequence, in the absence of these genomic resources an alternate approach uses platforms developed for model plant species. To assess transcriptome patterns associated with carotenoid pigmentation in carrot storage root, two carrot sibling inbred lines, B8788, true breeding for orange color and B8750, true breeding for white root color, were hybridized to the Medicago Affymetrix GeneChip microarray. Near isogenic recombinant inbred lines B8788 and B8750, derived from a cross between white rooted wild carrot (QAL) and orange-rooted B493 were used for comparative analyzes to minimize background genetic differences. B8788 is true breeding for orange color whereas B8750 is true breeding for white storage root color. Carrots were grown in three pots for each genotype under greenhouse conditions and carrots were selected arbitrarily from these pots for harvest. Roots were harvested at approximately 11 weeks post planting when carotenoid accumulation becomes apparent in the storage root. Storage root tissue from sixteen individual carrot roots was pooled into three one-gram tissue pools of four carrots for each genotype.
2014-08-13 | E-GEOD-49873 | biostudies-arrayexpress
Project description:Genome-wide transcription factor binding profiles provide valuable insights into hematopoietic development and malignancies. Today, advanced computational methods exploit cis-regulatory information to predict complex gene regulatory networks controlled by transcription factors. However, these prediction methods still require large amounts of reference data or experimental expertise. Here, we present a low-requirement network-based computational framework that exploits bidirectional transcription marked regulatory elements to identify important transcription factors driving hematopoietic decision making. Using CAGE-seq we predicted TF binding and confirmed experimentally validated TF important in cell conversion strategies by exploiting bidirectional regions. Next, we applied our framework to predict driving transcription factors in induced normal erythropoiesis and early myelopoiesis, as well as in acute myeloid leukemia associated MLL-AF9-driven immortalisation. Our approach allowed the identification of experimentally validated as well as thus far unexplored transcription factors in these processes.
2025-05-13 | GSE296865 | GEO
Project description:Autophagy is an intracellular degradation system that ensures a dynamic recycling of a variety of building blocks required for self-renewal, homeostasis, and cell survival under stress. We used primary acute myeloid leukemia (AML) samples and human AML cell lines to investigate the regulatory mechanisms of autophagy and its role in AML differentiation. We found a significantly lower expression of key autophagy- (ATG-) related genes in primary AML as compared to healthy granulocytes, an increased autophagic activity during all-trans retinoic acid- (ATRA-) induced neutrophil differentiation, and an impaired AML differentiation upon inhibition of ATG3, ATG4D, and ATG5. Supporting the notion of noncanonical autophagy, we found that ATRA-induced autophagy was Beclin1-independent compared to starvation- or arsenic trioxide- (ATO-) induced autophagy. Furthermore, we identified PU.1 as positive transcriptional regulator of ATG3, ATG4D, and ATG5. Low PU.1 expression in AML may account for low ATG gene expression in this disease. Low expression of the autophagy initiator ULK1 in AML can partially be attributed to high expression of the ULK1-targeting microRNA-106a. Our data clearly suggest that granulocytic AML differentiation relies on noncanonical autophagy pathways and that restoring autophagic activity might be beneficial in differentiation therapies.
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Project description:Microarrays transcriptomic data analyses from acute myeloid leukemia cell line OCI-AML2 and primary acute myeloid leukemia cells treated with actinomycin D.
2021-05-10 | E-MTAB-10397 | biostudies-arrayexpress
Project description:In this study, a cross species hybridization (CSH) approach was used to evaluate whole transcriptome changes during carotenoid accumulation in the storage root of carrot (Daucus carota). Carotenoids are isoprenoid compounds providing red, yellow and orange color to plants. Previous gene expression analyses of carotenoid accumulation in non-model plant species have primarily used a candidate gene approach. Since global transcriptome analyses require extensive genome sequence, in the absence of these genomic resources an alternate approach uses platforms developed for model plant species. To assess transcriptome patterns associated with carotenoid pigmentation in carrot storage root, two carrot sibling inbred lines, B8788, true breeding for orange color and B8750, true breeding for white root color, were hybridized to the Medicago Affymetrix GeneChip microarray.
2014-08-13 | GSE49873 | GEO
Project description:Most eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1. Rad23 and Ubx5 stimulate polyubiquitin binding to the 26S proteasome and the Cdc48-UN complex, respectively, allowing these machines to compete for substrates before and after their unfolding. Shp1 stimulates protein unfolding by the Cdc48-UN complex, rather than substrate recruitment. In vivo experiments confirm bidirectional substrate shuttling between the 26S proteasome and Cdc48 ATPase and identify proteins that require both machines for their degradation.
2024-02-23 | PXD042878 | Pride
Project description:Therapy-related acute myeloid leukemia (t-AML) often exhibits adverse (genetic) features. There is ongoing discussion on the impact of t-AML on long-term outcome in AML. Therefore, we retrospectively analyzed clinical and biological characteristics of 1133 AML patients (225 t-AML patients and 908 de novo AML patients) with a median follow-up of 81.8 months. T-AML patients showed more adverse genetic alterations, higher age and more comorbidities as compared to de novo AML. Median OS in intensively treated t-AML patients was 13.7 months as compared to 39.4 months in de novo AML (p < 0.001). With non-intensive therapy, OS did not differ significantly (p = 0.394). With intensive therapy, significant differences in favor of de novo AML were observed in the ELN intermediate I/II (p = 0.009) and adverse (p = 0.016) risk groups but not within favorable risk groups (APL p = 0.927, ELN favorable p = 0.714). However, t-AML was no independent risk factor for OS (p = 0.103), RR (p = 0.982) and NRM (p = 0.320) in the multivariate analysis. A limitation of our study is an ELN 2010 risk stratification due to a lack of more comprehensive molecular data according to ELN 2022. We conclude that therapeutic algorithms in t-AML, in particular with regard to allo-HSCT, should be guided by ELN genetic risk rather than classification as t-AML alone. Our data support the WHO and ICC 2022 classifications, which include t-AML as diagnostic qualifier rather than a separate subcategory.
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