Dataset Information

Genome-scale integrated analysis to identify prospective molecular mechanisms and therapeutic targets in isocitrate dehydrogenase 2 R140Q-mutated acute myeloid leukemia.

ABSTRACT: The aim of the present study was to identify potential molecular mechanisms and therapeutic targets in regards to isocitrate dehydrogenase 2 (IDH2) R140Q-mutated acute myeloid leukemia (AML). An RNA sequencing dataset of IDH2 wild-type and R140Q-mutated adult de novo AML bone marrow samples was obtained from The Cancer Genome Atlas (TCGA) database. The edgeR package was used to screen for the differentially expressed genes (DEGs), and the potential molecular mechanisms and therapeutic targets were identified using Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8, Biological Networks Gene Ontology tool, Connectivity Map (CMap), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and GeneMANIA. A total of 230 DEGs were identified between the bone marrow tissues of IDH2 R140Q-mutated and wild-type AML patients, of which 31 were significantly associated with overall survival (OS). Functional assessment of DEGs showed significant enrichment in multiple biological processes, including angiogenesis and cell differentiation. STRING and GeneMANIA were used to identify the hub genes of these DEGs. CMap analysis identified 13 potential small-molecule drugs against IDH2 R140Q-mutated adult de novo AML. Genome-wide co-expression network analysis identified several IDH2 R140Q co-expressed genes, of which 56 were significantly associated with AML OS. The difference in IDH2 mRNA expression levels and OS between the IDH2 R140Q-mutated and wild-type AML were not statistically significant in our cohort. In conclusion, we identified several co-expressing genes and potential molecular mechanisms that are instrumental in IDH2 R140Q-mutated adult de novo AML, along with 13 candidate targeted therapeutic drugs.

SUBMITTER: Huang R

PROVIDER: S-EPMC6448125 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-scale integrated analysis to identify prospective molecular mechanisms and therapeutic targets in isocitrate dehydrogenase 2 R140Q-mutated acute myeloid leukemia.

Huang Rui R Liao Xiwen X Li Jing J Wei Jiemin J Su Xiayun X Lai Xiaoxuan X Liu Beicai B Zhu Fangxiao F Huang Yumei Y Li Qiaochuan Q

Oncology reports 20190318 5

The aim of the present study was to identify potential molecular mechanisms and therapeutic targets in regards to isocitrate dehydrogenase 2 (IDH2) R140Q-mutated acute myeloid leukemia (AML). An RNA sequencing dataset of IDH2 wild-type and R140Q-mutated adult de novo AML bone marrow samples was obtained from The Cancer Genome Atlas (TCGA) database. The edgeR package was used to screen for the differentially expressed genes (DEGs), and the potential molecular mechanisms and therapeutic targets we ...[more]

PMID: 30896832

Similar Datasets

Project description:Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to ?-ketoglutarate (?-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of ?-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.

Project description:PurposeIvosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.Patients and methodsThis was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922).ResultsTwenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission.ConclusionIvosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.

Dataset Information

Genome-scale integrated analysis to identify prospective molecular mechanisms and therapeutic targets in isocitrate dehydrogenase 2 R140Q-mutated acute myeloid leukemia.

Publications

Genome-scale integrated analysis to identify prospective molecular mechanisms and therapeutic targets in isocitrate dehydrogenase 2 R140Q-mutated acute myeloid leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets