Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA192434 | ENA |
REPOSITORIES: ENA
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Project description:Transient low-dose decitabine treatment of primary AML samples
| PRJNA175142 | ENA
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex and monosomy karyotype (CK/MK) show high prevalence of TP53 mutations, poor response to induction chemotherapy and adverse patient outcome. These diseases may respond to decitabine but the mechanisms are presently unclear. MDS/AML patients were treated with decitabine for 10 days in a Phase II clinical study. In this study, we collected serial samples from patients before and at completion of decitabine treatment, morphologic remission and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations. The integrative analysis allowed characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Comparison of these trends between TP53 mutated MDS/AML patients who responded to treatment versus TP53 wildtype patients who were refractory to treatment highlighted the complex interplay of leukemic and immune compartments. Single cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed up-regulation of MYC signaling and heat shock response while T-cells showed exhaustion signature. Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.
2025-02-10 | GSE279925 | GEO
Project description:Acute myeloid leukemia (AML), and other myeloid malignancies, are frequently treated with hypomethylating agents like decitabine. Alterations in the epigenome, induced by decitabine, are likely to result in gene expression changes. The effects of decitabine have not been systemically studied using primary AML samples. We cultured 18 different primary AML samples for 7 days, the last 3 days of which included 100 nM decitabine (DAC) or 100 nm cytarabine (AraC). We hypothesized that decitabine treatment would result in detectable and consistent gene expression changes. For comparison, we also analyzed mRNA from cells treated with DMSO control (mock) and mRNA from uncultured cells taken at the time of diagnosis.
2012-12-18 | E-GEOD-40442 | biostudies-arrayexpress
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:Epigenetic changes play a role in the pathogenesis of myeloid malignancies and hypomethylating agents have shown efficacy in these diseases. We studied the apoptotic effect, the genome-wide methylation and gene expression profiles in HL60 cells following decitabine treatment, using micro-array technologies. Decitabine treatment resulted in a decrease in global DNA methylation, corresponding to 4876 probeset IDs with significantly reduced methylation levels, while expression of 2583 IDs was induced. The integrated analysis identified 160 genes demethylated and upregulated by decitabine, mainly including development and differentiation pathways genes. Genes target of polycomb group protein regulation were overrepresented in this group. Apoptosis was induced by decitabine and apoptosis-specific PCR arrays more precisely indicated decitabine-induced upregulation of 13 apoptosis-related genes, in particular Dap-kinase 1 and Bcl2L10. Correspondingly, in primary patient samples, BCL2L10 was hypermethylated in 45% of AML, 43% of therapy-related myeloid neoplasms, 12% of MDS and in none of the controls.
2010-09-21 | GSE24224 | GEO
Project description:Purpose: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS). Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy and inhibit clonogenic potential. We conducted a randomized study of decitabine when used as priming before standard induction therapy in children with newly diagnosed acute myelogenous leukemia (AML) to evaluate the safety, pharmacokinetics, and any potential early efficacy signal. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) were included to elucidate possible biological mechanisms. Methods: This multicenter, randomized, two-arm, open-label study enrolled children ages 1-16 with newly diagnosed de novo AML to either Arm A: daunorubicin, cytarabine, etoposide preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (control). Following completion of induction therapy, subsequent post-induction treatment was given at the treating physician’s discretion. Patients were monitored for adverse events and samples were collected for PK/PD and biologic analyses. Results: Twenty patients, ages 1-16 years (median 9.4 yrs in both Arms) were treated (10 per Arm). Eighteen of 20 enrolled subjects completed the prescribed treatment. All subjects experienced neutropenia and thrombocytopenia as is expected during AML induction chemotherapy. The most common grade 3 and 4 non-hematologic adverse events observed were caecitis, 2 (20%) subjects in Arm A and 0 (0%) subjects in Arm B; decreased appetite, 3 (30%) subjects in Arm A and 0 (0%) subjects in Arm B; and hypophosphatemia, 2 (20%) subjects in Arm A and 0 (0%) subjects in arm B. One subject in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation; the cause was later determined to have been leukemic infiltrate of the bowel wall. Two subjects died (both in Arm A), one of necrotic bowel, pseudomonas sepsis and multisystem organ failure 6 months after study participation and one patient 5 months following study treatment from multisystem organ failure as a complication of stem cell transplant. Plasma concentrations of decitabine showed PK values (mean+SD) of Cmax, 281+113 ng/mL, AUC0-∞, 198+65.3 ng*h/mL, CL, 156+94.6 L/h, Vdss 109+70 L, t1/2 0.48+0.060 h, and median tmax 0.93 h. Overall CR/CRi by morphology was similar between the two treatment arms (92% for the control arm and 100% for the experimental arm). MRD at Day 30 post induction therapy was lower in the control group compared to the decitabine group (67% vs 85% MRD-negative). Changes in DNA epigenetic and RNA expression patterns demonstrated distinct differences involving selective cellular pathways between the two groups of patients comparing diagnostic to day 30 bone marrow samples. Conclusions: This first-in-pediatric trial of epigenetic priming in patients with newly diagnosed AML demonstrates that decitabine pre-treatment followed by standard combination chemotherapy is well tolerated in children with newly diagnosed AML. Morphologic complete responses were similar in both treatment arms. MRD at Day 30 following induction therapy suggests a deeper remission in patients receiving decitabine. No differences were observed between treatment arms in hematologic toxicities although decitabine-treated patients were noted to have more gastrointestinal toxicities, anorexia and hypophosphatemia. Decitabine PK parameters in children were consistent with known adult PK profiles. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Pre-treatment with decitabine may represent a therapeutic option for use in pediatric AML, when epigenetic modification is a desired focus for treatment.
2017-10-31 | GSE78963 | GEO
Project description:Acute myeloid leukemia (AML), and other myeloid malignancies, are frequently treated with hypomethylating agents like decitabine. Alterations in the epigenome, induced by decitabine, are likely to result in gene expression changes. The effects of decitabine have not been systemically studied using primary AML samples.
2012-12-18 | GSE40442 | GEO