Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified a novel fusion partner of MLL, namely the mastermind like 2 (MAML2 gene), in secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with inv(11)(q21q23). RT-PCR and sequencing revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the NH2-terminal part of MLL and 952 amino acids from the COOH-terminal part of MAML2. The NH2-terminal part of MAML2, a basic domain including a binding site of the intracellular domain of NOTCH, was deleted in MLL-MAML2. MLL-MAML2 in secondary AML/MDS and MECT1-MAML2 in mucoepithelioid carcinoma, benign Wartin's tumor, and clear cell hidradenoma consist of the same COOH-terminal part of MAML2. A luciferase assay revealed that MLL-MAML2 suppressed HES1 promoter activation by the NOTCH1 intracellular domain. MAML2 involving a chimeric gene might contribute to carcinogenesis in multiple neoplasms by the disruption of NOTCH signaling.
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PMID:Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23). 1755 48

Delta-like-1 (Dlk1, also Pref-1), a transmembrane and secreted protein, is a member of the epidermal growth factor-like family, homologous to Notch/Delta/Serrate. We found that the expression of Dlk1 was up-regulated in CD34+ cells from patients with myelodysplastic syndrome (MDS) by analyzing the gene expression profiles determined by microarray. The expression levels of Dlk1 mRNA frequently observed higher in the bone marrow mononuclear cells of MDS patients was confirmed by real-time RT-PCR. Forced expression of Dlk1 in transfected K562 cells enhanced proliferation, affected apoptosis induced by As2O3, and also influenced cell cycle induced by 12-O-tetra decanoylphorbol-acetate (TPA). By using the same experimental system we found that forced expression of Dlk1 increased the mRNA levels of HES1. It also inhibited p38 phosphorylation in transfected K562 cells treated with TPA. These results warrant further investigation of the role of Dlk1 in abnormal hematopoiesis in MDS.
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PMID:Expression of Dlk1 gene in myelodysplastic syndrome determined by microarray, and its effects on leukemia cells. 1857 77

Myelodysplastic syndromes (MDS) are characterized by dyserythropoiesis resulting in anemia. This pathological hallmark is incompletely understood. Notch signaling has been linked to impaired erythropoietic and megakaryopoietic development of CD34+ progenitor cells, but its role in MDS is unclear. We have analyzed the transcriptional activity of Notch pathway elements and its association with the key erythroid factor globin transcription factor 1 (GATA1) and the apoptosis regulatory gene B-cell lymphoma-xl (BCLxl) in MDS. The methylation of GATA1 erythroid promoter CpG dinucleotides flanking cis-regulatory elements, including an N-box suppressor binding site for HES1 and a GATA-box binding site, was examined in normal and MDS erythropoiesis. We have generated a kinetic in vitro model of MDS erythropoiesis using CD34+ bone marrow cells from healthy donors (n = 7) and patients with MDS (low risk: RA/n = 6, RARS/n = 3; high risk: RAEB/n = 4, RAEB-T/n = 2). RNA expression of GATA1, BCLxl, DLK1, Notch1, HES1, and HERP2 was measured by real-time RT-PCR (qPCR). DNA methylation at seven CpG dinucleotides of the GATA1 gene promoter was quantitatively analyzed by pyrosequencing of bisulfite-treated genomic DNA at any specific time point. For the Notch pathway elements, no conclusive expression differences were found between MDS and normal erythropoiesis. But we found steadily up-regulated RNA expression of GATA1 and of BCLxl during late normal erythropoietic differentiation. In contrast, during MDS, erythropoiesis a loss of typical up-regulation of GATA1 and BCLxl was observed. Hypermethylation of CpG dinucleotides flanking the repressor HES1 binding site within the 5' region of GATA1 was detected particularly during late MDS erythropoiesis. Interestingly, decremental GATA1 promotor methylation values were seen during normal erythropoiesis matching GATA1 RNA up-regulation. Our data show that the critical erythropoietic transcription factor GATA1 as well as the antiapoptotic molecule BCLxl fails to be normally up-regulated during MDS erythropoiesis. The higher residual 5'-GATA1 methylation values in MDS erythropoiesis but decremental loss thereof in normal erythropoiesis suggest a gene dose effect for GATA1 during erythropoiesis being finely tuned by CpG methylation. Its dysregulation may contribute to the ineffective erythropoiesis observed in MDS.
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PMID:Epigenetic dysregulation of GATA1 is involved in myelodysplastic syndromes dyserythropoiesis. 2196 5

Bone marrow niche constituents have been implicated in the genesis of clonal hematopoietic dysfunction in myelodysplastic syndromes (MDS), though the exact role of stroma in the pathogenesis of MDS remains to be defined. We have evaluated the characteristics of mesenchymal stromal cells in a cohort of patients with MDS with multilineage dysplasia (MDS-MLD). MSCs were cultured from bone marrow aspirates of MDS-MLD patients and controls with healthy bone marrow. Phenotypic characterization, cell cycle, and apoptosis were analyzed by flow cytometry. Targeted gene expression analysis was done using a reverse-transcription polymerase chain reaction (Q-PCR). MSCs derived from MDS patients (MDS-MSCs) showed normal morphology, phenotype, karyotype and differentiation potential towards adipogenic and osteogenic lineages. However, these MDS-MSCs showed significantly altered cell cycle status and displayed a shift towards increased apoptosis compared to control MSCs (C-MSCs). The gene expression profile of niche responsive/regulatory cytokines showed a trend towards lower expression VEGF, SCF, and ANGPT with no changes in expression of CXCL12A and LIF compared to C-MSCs. The expression levels of Notch signaling components like Notch ligands (JAGGED-1 and DELTA-LIKE-1), receptors (NOTCH1, NOTCH3) and downstream gene (HES1) showed an aberrant expression pattern in MDS-MSCs compared to C-MSCs. Similarly, Q-PCR analysis of Wnt signaling inhibitory ligands (DKK-1 and DKK-2) in MDS-MSCs showed a three-fold increase in mRNA expression of DKK1 and a two-fold increase in DKK2 compared to C-MSCs. These data suggested that MDS-MSCs have an altered proliferation characteristic as well as a dysregulated cytokine secretion and signaling profile. These changes could contribute to the pathogenesis of MDS.
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PMID:Heterogeneity of Mesenchymal Stromal Cells in Myelodysplastic Syndrome-with Multilineage Dysplasia (MDS-MLD). 3098 56