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)

Immunemediated hematopoietic suppression has been considered as one of significant pathophysiological changes in less-advanced myelodysplastic syndrome (MDS). To explore deviation of T cell subsets and its relationship to marrow cells apoptosis, measurement of helper-T (Th)/cytotoxic-T (Tc) subsets as well as the deviation situation within this two subsets (Th1/Th2 and Tc1/Tc2) in marrow was performed by flow cytometry from 39 MDS patients and 13 normal controls. Interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha in marrow serum was simultaneously detected by ELISA (enzyme-linked immunosorbent assay). Furthermore, apoptosis rate of marrow cells was demonstrated by TUNEL (TdT-mediated dUTP nick end labeling). Results showed that Th and Tc subsets were unevenly activated, both deviating to type I response, which was especially obvious in patients with RCMD (according to WHO classification) and in lower-risk cases defined by International Prognosis Scoring System (IPSS). Level of INF-gamma/TNF-alpha in MDS marrow serum was markedly elevated, and so did the apoptosis rate of marrow cells. Although type I deviation was observed both in Th and Tc subsets, just Th1 cell percentage showed positive correlation with level of INF-gamma/TNF-alpha and apoptotic index of nucleated cells. In addition, cytokines level in marrow serum presented positive correlation to apoptosis. We then deduced that the increased Th1 cells in marrow may account for nucleated cells apoptosis in MDS through overproduced proapoptotic cytokines such as INF-gamma and TNF-alpha. Our results suggested that type I deviation of T cell subsets may play a role in pantocytopenia in MDS and the deviation pattern may be as a direct and effective parameter to predict response of immunosuppression therapy.
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PMID:Deviation of type I and type II T cells and its negative effect on hematopoiesis in myelodysplastic syndrome. 1904 14

Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.
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PMID:BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells. 2394 52

The mechanisms of platelet underproduction in immune thrombocytopenia (ITP) remain unknown. While the number of megakaryocytes is normal or increased in ITP bone marrow, further studies of megakaryocyte integrity are needed. Megakaryocytes are responsible for the production of platelets in the bone marrow, and they are possible targets of immune-mediated injury in ITP. Since the biological process of megakaryocyte apoptosis impacts platelet production, we investigated megakaryocyte DNA fragmentation as a marker of apoptosis from ITP bone marrow biopsies. Archived bone marrow biopsy specimens from ITP patients, bone marrow specimens from controls with normal platelet counts, and bone marrow specimens from thrombocytopenic controls with myelodysplastic syndrome (MDS) were evaluated. Sections were stained with anti-CD61 for megakaryocyte enumeration, and terminal deoxynucleotidyl transferase dUTP nick-end labeling was used as an apoptotic indicator. In ITP patients, megakaryocyte apoptosis was reduced compared to nonthrombocytopenic controls. Megakaryocyte apoptosis was similarly reduced in thrombocytopenic patients with MDS. These results suggest a link between megakaryocyte apoptosis and platelet production.
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PMID:Megakaryocyte apoptosis in immune thrombocytopenia. 2978 28


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