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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of protooncogenes (ras, fms and myc genes) by point mutations in hematological malignancies are described in this review. Ras mutations are found in a variety of human malignancies at codon 12, 13, and 61. Generally, N-ras mutations are frequent in hematological malignancies. Fms mutation at codon 301 and 969, which are seen in 10 to 20% cases of AML and MDS, increase tyrosine kinase activity of the fms products. Ras and fms mutations are postulated to influence leukemogenesis at rather early stages. Burkitt lymphomas are characterized by specific chromosomal translocations between c-myc gene and one of the immunoglobulin genes. Furthermore, mutations in the 3' border of the exon 1 of c-myc are frequent, and may play an additional role in pathogenesis of Burkitt lymphoma.
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PMID:[Activation of protooncogenes by point mutations in hematological malignancies]. 151 54

We studied myelodysplastic syndrome-associated inhibitory activity (MDS-IA), which inhibited colony formation in vitro of normal granulocyte-macrophage progenitors (CFU-GM). When adherent marrow cells were incubated with fetal calf serum for 21-24 d, monocyte-derived lipid containing huge macrophages (MDLM) developed. MDLM from MDS marrow (MDS-MDLMs) and their conditioned medium (MDLM-CM) consistently suppressed the growth of normal CFU-GM colony formation. MDS-IA was active on CFU-GM during the S-phase and relatively resistant to heating. Monoclonal antibody against H subunit (acidic) ferritin and polyclonal antibody against placental ferritin neutralized the inhibitory activity of MDS-MDLMs. In addition, cell lysates of MDS-MDLMs reacted to both monoclonal anti-H subunit ferritin and polyclonal anti-placental ferritin in Western blotting analysis, indicating that the inhibitory activity was predominantly acidic isoferritin. On the other hand, MDLMs obtained from normal bone marrow had a CFU-GM enhancing activity. These results suggest that MDS-MDLMs may be responsible for the suppression of granulopoiesis in patients with MDS and that the suppression may be mediated by soluble factors, notably H subunit isoferritin.
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PMID:Myelodysplastic syndrome (MDS)-associated inhibitory activity on haematopoietic progenitor cells: contribution of monocyte-derived lipid containing macrophages (MDLM). 152 Jun 27

Coexistence of myeloma and MDS was noted in a patient without history of exposure to cytotoxic drugs. A 73-year-old man was admitted because of fever and dyspnea on exertion. A complete blood count revealed macrocytic anemia with hemoglobin 7.1 g/dl, RBC 191 x 10(4)/microliters and MCV 111.2 fl. WBC was 6,000/microliters, with normal differentials. Bone marrow showed erythroid hyperplasia with M/E ratio of 1.36. There were marked tri-lineage cellular abnormalities, which included megaloblastic changes, multinucleated erythroblasts, hypersegmentation of neutrophils, giant neutrophils, and giant platelets. Ringed-sideroblasts were demonstrated in 20% of the erythroblasts. These findings were compatible with MDS. Although plasma cells accounted for only 9.7% of the nucleated marrow cells, there were many immature plasma cells with inclusion bodies, and the patient showed lambda-light chain type monoclonal gammopathy with corresponding Bence Jones protein. Immuno-histochemical staining of the bone marrow biopsy specimen revealed monoclonal growth of lambda-positive plasma cells. A punched-out lesion of the skull eventually developed. These findings suggest existence of myeloma. There have been some reports of coexistence of MDS and myeloma; supporting the idea of pluripotent stem cell origin of the disease. This is the first documentation of such a case in Japan.
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PMID:[Coexistence of myeloma and primary myelodysplastic syndrome (MDS)]. 154 17

We studied dysplastic features in peripheral blood polymorphs from 80 patients with acute leukaemia. Thirty-seven patients with de novo acute myeloblastic leukaemia (AML) were compared to 26 patients with AML that had developed after a myelodysplastic phase (MDS-AML), and 17 cases of acute lymphoblastic leukaemia (ALL). Cytoplasmic hypogranulation in neutrophils, measured as a score value (G-score; normal range: 255-300), and the percentage of pelgeroid polymorphs (ppp; normal range: 0.5%) were studied retrospectively by reviewing the diagnostic peripheral blood smears. The mean G-score was decreased in MDS-AML (178 +/- 67.9), and in de novo AML (212 +/- 65.1), but not in ALL (275 +/- 24.3). When de novo AML patients were divided by age, the elderly (greater than 60 yr) had significantly (p = 0.0001) lower mean G-score than the younger (less than 45 yr) ones; 156 +/- 64.8 v 243 +/- 41.4. This age-related difference became accentuated when only patients with extreme hypogranulation (G-score less than 150) were studied. Elderly de novo AML patients also had significantly (p = 0.0057) higher mean ppp. By studying the degree of polymorph dysplasia in the peripheral blood, it seems possible to identify a subset of dysplastic elderly AML patients, who might have passed a (preleukaemic) MDS phase unnoticed.
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PMID:Dysplastic peripheral blood polymorphs link acute myeloblastic leukaemia in elderly to the myelodysplastic syndromes. 155 74

Aggressive chemotherapy of myelodysplastic syndromes is rarely feasible because these disorders predominantly occur in elderly patients who often have concurrent illnesses. Alternative treatment modalities must therefore be evaluated. This review summarizes the results that have been obtained with low-dose chemotherapy, especially with low-dose cytosine arabinoside (Ara-C). Overall response rates to treatment with low-dose Ara-C are about 40%, with some 20% of patients achieving a complete remission. Transition of MDS to AML does not reduce the probability of response. The therapeutic outcome cannot be reliably predicted by clinical or experimental parameters. Hematological toxicity is substantial, with approximately 10-25% treatment-related deaths. Duration of response is short and rarely exceeds one year. In terms of overall survival, low dose Ara-C does not appear to be superior to supportive care only. Other cytotoxic agents have not been studied in detail, but data available do not suggest an appreciable advantage over Ara-C. Before denying low-dose chemotherapy a helpful role in MDS, randomized studies should concentrate on those patients who can be expected to derive the greatest benefit. Because of their short survival, patients with RAEBt or those transformed to overt leukemia are such candidates.
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PMID:The role of low-dose chemotherapy in myelodysplastic syndromes. 156 Jun 70

We report two patients with a myelodysplastic syndrome and the Philadelphia (Ph) chromosome. The first patient was a 73-year-old man who was diagnosed as having a chronic myelomonocytic leukemia in combination with features suggestive of a myeloproliferative syndrome. Chromosomal analysis showed a normal karyotype in the majority of cells, mixed with metaphases containing a standard Ph translocation, t(9;22)(q34;q11), as well as a translocation between chromosome 4 and 6: t(4;6)(p15;p12). Southern blot analysis showed breakpoint cluster region rearrangement as observed in classic chronic myeloid leukemia. The second patient was a 63-year-old man with a myelodysplastic syndrome, type refractory anemia. Cytogenetic study of bone marrow cells at the time of diagnosis revealed a normal karyotype: 46,XY. The initial myelodysplastic syndrome evolved to a myeloproliferative phase with progressive leukocytosis and thrombocytosis. During the terminal phase the Ph chromosome was discovered in 100% of the examined cells. We discuss the correlation between MDS and myeloproliferative diseases, the de novo acquisition of the Ph chromosome during the course of a myelodysplastic syndrome, and review the literature.
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PMID:Cytogenetic and molecular studies of the Philadelphia translocation in myelodysplastic syndromes. Report of two cases and review of the literature. 158 81

The frequency of non-clonal structural and numerical chromosome aberrations in peripheral blood lymphocytes of 51 patients with MDS and 37 age-matched hematologically normal subjects is assessed. The frequency of aneuploid cells (p less than 0.001) and of structural aberrations (p less than 0.005) was significantly higher in MDS patients than in normal subjects, but showed no relationship with FAB type or with the presence of clonal karyotype abnormalities in the bone marrow. Exchange configurations were only observed in MDS patients (27.5%). The data also suggest that there may be an association between high peripheral blood aberration levels and rapidly progressive disease. This may indicate increased mutagen sensitivity and have implications for treatment.
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PMID:Peripheral blood chromosome aberrations in MDS. 158 82

In a retrospective study of 352 patients with primary myelodysplastic syndromes, 61 (17.3%) revealed myelofibrosis in bone marrow biopsies. The fibrosis was observed to occur mostly focally (41/61 cases), and collagen deposits were found very rarely (4/61). The histopathology of bone marrow biopsies revealed hyperplasia and disturbed differentiation in megakaryopoiesis; the frequency and grade of dysplasia in megakaryopoiesis increased with advancing myelofibrosis. Reticulin fibrosis occurred in all subtypes of MDS; however, there was a higher incidence in chronic myelo-monocytic leukaemia (CMMoL). The frequency of cytogenetic aberrations was significantly higher in the MDS cases with myelofibrosis, compared to the cases without fibrosis. Clinical data showed significantly lower values of haemoglobin and lower platelet counts in MDS with myelofibrosis. Life expectancy was reduced to 9.6 months, compared with 17.4 months in MDS without fibrosis. In refractory anaemia, the survival times were 10.0 months in MDS with myelofibrosis, compared to 28.9 months in MDS without myelofibrosis. 36.6% of the patients with MDS and myelofibrosis developed a transformation into ANLL during the course of the disease. Myelofibrosis therefore seems to herald a poor prognosis.
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PMID:Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. 159 1

In vitro clonogenic assays of bone marrow have provided invaluable information about the complex regulatory mechanisms controlling hematopoiesis, both normal and abnormal, and have led to the discovery of colony stimulating factors. Our understanding of the abnormalities of growth and differentiation characterizing the MDS have been advanced largely through use of these assays. Abnormalities commonly seen in cultures of marrow from patients with MDS include decreased or absent colony growth, abortive cluster formation, and defective maturation of cells within the colonies. Although some investigators have defined growth patterns as "leukemic" and "nonleukemic" and have tried to correlate growth patterns with potential for evolution to acute leukemia, these methods are difficult to apply to any given case. Given the wide variety of techniques used to collect cells and the lack of standard sources for stimulating growth factors, the results, not surprisingly, have been inconclusive in predicting both prognosis and progression to acute leukemia. New methods by which clonogenic assays can be standardized, such as purification of the clonogenic cells and use of recombinant growth factors, should allow these assays to advance our understanding of MDS, develop new therapies, and predict responses to therapy in individual patients.
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PMID:In vitro hematopoiesis in myelodysplasia: liquid and soft-gel culture studies. 161 5

Myelodysplastic syndromes originate from a pluripotent stem cell. This view, previously suggested by G-6-PD and cytogenetic investigations, has been established unequivocally by X-chromosome inactivation analysis based on DNA polymorphisms and by studies of mutated oncogenes. Two genomic alterations associated with MDS have been analyzed in more detail. Activation of the RAS oncogenes, preferentially N-RAS, is demonstrated in approximately 35% of MDS patients. Mutations in the FMS gene, encoding the CSF-1 receptor, are found in 16% of cases. Interestingly, RAS and FMS mutations are predominantly observed in disorders of myelomonoctic differentiation, i.e., the CMML subtype in MDS and the AML FAB type M4. Moreover, homozygous deletion of the FMS gene may be an important event in the genesis of the MDS variant 5q- syndrome. Preliminary data indicate that defects in tumor-suppressor genes, namely p53, may also contribute to the development of MDS. Different lines of evidence suggest that clinical preleukemia is preceded by a phase in which genetic alterations accumulate without any hematologic change. Cases in point are the detection of RAS and FMS mutations in healthy individuals who had been treated in the past with cytotoxic therapy for lymphoma, the frequent observation of clonal remission in AML patients, or the identification of oncogene mutations in healthy individuals without even a history of malignancy or chemotherapy. Possibly, either germline mutations of oncogenes or tumor-suppressor genes and the process of genomic imprinting may constitute additional factors that predispose hematopoietic stem cells to malignant transformation. Limited as they are, the currently available data suggest that accumulation of genomic lesions, rather than their precise order of development with respect to one another, characterize the multistep process of leukemogenesis in which MDS already represent more advanced stages. The prognostic significance of oncogene mutations in MDS patients is controversially discussed. This issue awaits prospective analyses taking into account the influence of treatment modalities. However, the clinical relevance of molecularly defined parameters has already been established for their use as clonal markers in determining the mode of action and efficiency of different therapeutic approaches.
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PMID:Molecular genetic aspects of myelodysplastic syndromes. 161 6


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