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)

The haematological diversity of myelodysplastic syndromes (MDS) mandates that therapeutic strategies for this disease be guided by an understanding of the disease biology. Insights into the pathobiology of this disease have given rise to novel treatment strategies which exploit basic biological disturbances. Myelodysplastic bone marrow progenitors from patients with low leukaemia burden display an accelerated senescence phenotype which is characterised by impaired response to trophic signals and premature apoptotic death of primitive haematopoietic progenitors. Elaboration of aptogenic cytokines such as TNF-alpha and IL-1beta may reinforce this sequence by up-regulating cellular expression of fas ligand and its cognate receptor, suppressing responsiveness to growth factor stimulation, and accelerating apoptotic cell death. Inactivation of p15 or other tumour suppressor genes antedate disease progression and the emergence of blast populations with reduced capacity for fas mediated cell death. Herein we review the current understanding of the pathobiology of MDS and promising strategies for therapeutic intervention.
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PMID:Pharmacological differentiation and anti-apoptotic therapy in myelodysplastic syndromes. 1010 Dec 9

The paradox of peripheral cytopenias despite a normo/hypercellular marrow in MDS has been ascribed to excessive intramedullary hematopoietic cell apoptosis. Programmed cell death (PCD) in early disease might be triggered by the BM microenvironment, mediated either through inhibitory cytokines such as tumor necrosis factor alpha (TNF-alpha) or fas/fas ligand signaling or through a relative deficiency in hematopoietic growth factors. Intrinsic cellular defects giving rise to abnormalities in cell-cell or cell-stromal interaction, cell signaling or cell cycling may also underlie hematopoietic progenitor apoptosis. Alternatively, an early 'hit' in the multistep pathogenesis of MDS may result in a higher proliferative rate of the neoplastic clone. Increased apoptosis may thus represent a homeostatic process to control cell numbers. This paper shall summarize current evidence implicating a role for increased PCD in low risk MDS, outline possible etiologic factors and suggest potential therapeutic mechanisms whereby excessive hematopoietic progenitor cell apoptosis might be circumvented.
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PMID:Excessive apoptosis in low risk myelodysplastic syndromes (MDS). 1142 9

Aplastic anaemia seems to be predominantly a defect of the stem cell rather than the stroma, though abnormalities of the microenvironment may co-exist. There is highly suggestive evidence that the stem cell is the target of an immune attack, though the main evidence remains the response to immunosuppression with antilymphocyte globulin and cyclosporin. The stem cell defect remains even after recovery of the peripheral blood counts and the AA marrow is a fertile environment for the emergence of abnormal clones, particularly PNH. However, it has recently become apparent that there is an overlap with the myelodysplastic syndromes and clones of monosomy 7 and trisomy 8 amongst others are not uncommon in aplastic anaemia. Recent work has suggested that the emergence of a clone of monosomy 7 cells carries a poor prognosis, whereas trisomy 8 has a good prognosis particularly in response to cyclosporin. However, the setting in which monosomy 7 arises may affect the phenotypic expression. The immune targeting of stem cells may be associated with increased apoptosis in aplastic anaemia, in part mediated by fas expression, but not exclusively. Understanding the pathophysiology of AA should help to improve and perhaps target therapy.
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PMID:Views on the pathophysiology of aplastic anaemia. 1243 Sep 19