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)

All-trans retinoic acid (ATRA) and granulocyte colony stimulating factor (GCSF) are potential inducers of myeloid progenitor cell growth and neutrophil differentiation in myelodysplasia (MDS). We have compared the effects of ATRA and GCSF on the colony growth of 10 MDS marrows, in semi-solid and liquid serum-free mononuclear cell (MNC) cultures, supplemented with a mixture of stem cell factor (SCF), interleukin 3 (IL-3) and granulocyte-monocyte colony stimulating factor (GmCSF) (SIGm mix), which is fully-supportive for myeloid and erythroid (with erythropoietin (EPO)) colony formation in normal marrow. Only 1/10 MDS patients produced normal granulocyte-macrophage colony-forming cell (GmCFC) numbers, under SIGm conditions and erythroid colonies (ECFC) were subnormal in all patients. ATRA (10(-7) M) increased GmCFC numbers (P=0.05) in semi-solid cultures of normal, but not MDS marrow MNC and decreased erythroid colonies in cultures of marrow from either source (P=0.008 and P=0.0001 for normal and MDS, respectively). ATRA enhanced neutrophilic maturation in liquid cultures of both normal and myelodysplastic CD34 + ve cells, as detected by conventional morphology and acquisition of CD15. In contrast to ATRA, GCSF increased Gm colony size but not numbers in semi-solid cultures of normal marrow MNC, which suggests the cytokine augments post-progenitor amplification. This would explain why GCSF increased cell yields in liquid cultures of normal and MDS MNC while GmCFC accumulation remained unchanged. GCSF, though, increased Gm colony numbers in semi-solid cultures of MDS marrow MNC (P=0.014) so that 4/10 patients now grew colonies within the normal range. This was again probably due to increasing clone size, so that some clusters, the numbers of which may be elevated in MDS, were now scored as colonies. Overall, these data indicate that ATRA can enhance the maturation of the progeny of MDS GmCFC whilst GCSF can augment their amplification.
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PMID:GCSF augments post-progenitor proliferation in serum-free cultures of myelodysplastic marrow while ATRA enhances maturation. 961 15

The levels of IL-1 alpha, IL-2, IL-6 and TNF-alpha were measured immunoradiometrically in the sera of 82 myelodysplastic (MDS) patients at diagnosis in an attempt to identify possible relationships between serum cytokine levels and clinical and laboratory parameters of the patients. We found that serum IL-6 and TNF-alpha concentrations were significantly higher in the group of MDS patients than in the normal controls (p < 0.03 and p < 0.001, respectively), while serum IL-1 alpha and IL-2 levels did not differ statistically between patients and control subjects. Elevated serum IL-6 and TNF-alpha concentrations were mainly seen in patients with high-risk myelodysplasia (MDS), i.e. patients with chronic myelomonocytic leukemia (CMML) (p < 0.05 and p < 0.001, respectively), refractor anemia with excess of blasts (RAEB) (p < 0.01 and p < 0.001, respectively), or refrochopy anemia with excess of blasts in transformation to acute leukemia (RAEB-t) (p < 0.001 and p < 0.001, respectively). Patients with low-risk disease, i.e. patients with refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS), had serum cytokine levels comparable to those of controls. Patients' serum IL-6 and TNF-alpha correlated inversely with the hemoglobin concentration (p < 0.01 and p < 0.05, respectively) and positively with the absolute number of circulating myeloblasts (p < 0.01 and p < 0.001, respectively) and the proportion of bone marrow (p < 0.001 and p < 0.001, respectively) myeloblasts. A negative correlation was also noted between serum TNF-alpha concentrations and patients' survival in high-risk MDS (p < 0.02). We concluded that elevated serum IL-6 and TNF-alpha values are seen mainly in patients with high-risk disease, and that high serum TNF-alpha concentrations are predictive of shortened survival in this group of patients.
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PMID:Elevated serum TNF-alpha concentrations are predictive of shortened survival in patients with high-risk myelodysplastic syndromes. 970 53

Recent efforts have been directed at improving the methodology for predicting clinical outcomes in patients with myelodysplastic syndromes (MDS). This review focuses on the development of a consensual, prognostic, risk-based analysis system generated by the International MDS Risk Analysis Workshop. In the workshop, cytogenetic, morphological, and clinical data were combined and collated from a relatively large group of patients with primary MDS. Critical prognostic variables were evaluated using the data set. Based on these findings, the International Prognostic Scoring System (IPSS) was developed, compared with other systems, and shown to provide more accurate prognoses regarding survival and evolution to acute myeloid leukemia in MDS patients. The improvement was due to several features of the workshop model: more refined cytogenetic categorization, inclusion of cytopenias, improved subdivision of marrow blast percentages, four subgroups defining outcome, and separate stratification for age. The IPSS should result in better-defined clinical outcomes in MDS and provide a framework for future studies determining the possible role of molecular determinants (e.g. oncogenes, tumor suppressor genes, cytokine expression and responsiveness) for evaluating prognoses. The IPSS will likely prove useful in the design and analysis of therapeutic trials in MDS as well as in patient management.
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PMID:Risk factors and their relationship to prognosis in myelodysplastic syndromes. 973 92

The expansion of myeloma cells is regulated by cytokines, among which IL-6 is a major growth factor. It has been recently suggested that serum transforming growth factor beta 1 (TGF beta 1), a cytokine found in large amounts in alpha-granules of platelets, might play a role in multiple myeloma (MM). It was the purpose of this study to determine serum TGF beta 1 levels in MM patients and to seek a correlation with disease parameters. Measurements were done by ELISA. We studied 35 MM patients (19 stage II, 16 stage III, 20 IgG, 8 IgA and 6 BJ, 1 IgD) in different phases of the disease, 27 healthy individuals and 17 thrombocytopenic patients with other haematological diseases (three MDS, three congenital thrombocytopenia, 11 ITP). Overall samples from MM patients were included: 10 at diagnosis, 18 in remission and 32 in relapse. In normal controls TGF beta 1 serum levels ranged from 1 to 33 ng/ml (median 16.5 ng/ml). In both thrombocytopenic controls with other diseases and thrombocytopenic MM patients (seven samples), TGF beta 1 serum levels were very low (median 3.2 and 4.5 ng/ml respectively). In MM patients with PLT > 100 x 10(9)/L (53 samples), TGF beta 1 serum levels were in the normal range in patients without immunoparesis (1 to 27 ng/ml, median 16.6 ng/ml), whereas they were higher in patients with immunoparesis (polyclonal immunoglobulins (Igs) below lower normal reference values) ranging from 10.2 to 45 ng/ml (median 26.8 ng/ml) (P < 0.01). Serum TGF beta 1 levels fluctuated in the same patient at different times but not according to relapse or remission. Correlation was found only between serum TGF beta 1 levels and immunoparesis and not between serum TGF beta 1 levels and disease stage or Ig subtype nor with prognostic factors for MM (serum CRP, beta 2M or IL-6). This finding suggests that the remaining normal plasma cells are sensitive to the inhibitory action of TGF beta 1 on Ig production. In conclusion TGF beta 1 serum levels are very low in thrombocytopenic patients confirming that platelets are the major source of this cytokine. Furthermore, a strong correlation was found between TGF beta 1 serum levels and immunoparesis in MM patients.
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PMID:Serum transforming growth factor-beta 1 is related to the degree of immunoparesis in patients with multiple myeloma. 978 21

Early clinical trials of growth factor augmentation of induction chemotherapy for acute myeloid leukemia have yielded variable results. To test the hypothesis that this heterogeneity is a consequence of the pleiotropic effects of growth factors on leukemic cell biology, we measured the effects of in vivo interleukin 3 (IL-3) administration on leukemic cell proliferation and drug sensitivity. Thirty-four patients with acute myeloid leukemia with high-risk features or advanced myelodysplasia received IL-3 as a continuous infusion beginning 3 days prior to chemotherapy and continuing for the duration of intensive induction therapy. Bone marrow cells were studied prior to and after 3 days of IL-3 administration to assess changes in overall and leukemic progenitor cell [leukemia colony-forming unit (CFU-L)] proliferation, and progenitor cell sensitivity to 1-betad-arabinofuranosylcytosine. The median fold increase in overall leukemic cell proliferation in response to IL-3, assessed as expression of the nuclear antigen Ki67 in 28 patients, was 1.2. The median fold increase in percentage of cells in S phase (assessed in 29 patients) was 1.3. Despite the increase in overall cell proliferation in 70% of cases, CFU-L number increased in only 4 of 20 patients successfully studied (median day 4:day 1 ratio of CFU-L number, 0.6). While this suggests possible terminal differentiation of leukemic progenitor cells, expression of CD34, HLA-DR, c-kit, CD15, and CD14 were not consistently affected by the cytokine. 1-betad-Arabinofuranosylcytosine sensitivity of CFU-L increased significantly in 30% of cases, decreased in 30%, and was unchanged in 40%. Changes in overall cell proliferation (Ki67 expression) and CFU-L were independent predictors of change in 1-beta-d-arabinofuranosylcytosine sensitivity; increase in percentage of cells in S phase in response to IL-3 was correlated with attainment of complete remission. While these findings support the concept of cell cycle recruitment, IL-3 has marked pleiotropic effects on proliferation, differentiation, and survival of leukemic progenitors which make the clinical impact of in vivo cytokine administration for individual patients difficult to predict.
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PMID:Impact of in vivo administration of interleukin 3 on proliferation, differentiation, and chemosensitivity of acute myeloid leukemia. 981 85

An 'initial transforming event(s)' in a pluripotential bone marrow (BM) stem cell confers a growth advantage upon it leading to clonal expansion accompanied by dysplastic maturation resulting in myelodysplastic syndromes (MDS). The nature of this 'initial' event in MDS is obscure. We propose that MDS can begin as a viral disease. It may be a dormant lentivirus which is made oncogenic by 'promoting events' such as immunosuppression, or a second viral infection. The infected cell may not be a BM stem cell, but a cell belonging to the BM stroma or to the immune system. Dysregulated cytokine production as a consequence of the infection can change the BM microenvironment in such a way that optimal growth support is provided only to a rapidly proliferating stem cell. Karyotypically marked (or unmarked) abnormal stem cells may exist or arise frequently but do not thrive in a 'normal' cytokine milieu. However, with the changed BM landscape, these abnormal clones may enjoy a growth advantage leading to a monoclonal hypercellular BM and variable cytopenias. Circumstantial evidence to support the possibility that the initial transforming event in MDS is a viral insult is presented in this hypothesis paper.
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PMID:Hypothesis: myelodysplastic syndromes may have a viral etiology. 984 9

Apoptosis (programmed cell death) is an active cellular process which regulates cell population size by decreasing cell survival. In this review the underlying cellular and molecular mechanisms of apoptosis in hemopoietic and non-hemopoietic cells are described, with specific focus on these issues in the myelodysplastic syndrome (MDS), a myeloid clonal hemopathy. Apoptosis-regulating genes exist as families whose protein products are either anti-apoptotic or pro-apoptotic. Numerous stimuli can serve as initiators of the cell death pathway, including essentially all chemotherapeutic drugs, irradiation, certain inhibitory cytokines and deprivation of relevant growth factors. Morphological evidence of increased apoptosis in marrow hemopoietic cells has been demonstrated in patients with MDS. The reviewed data provide support for the hypothesis that early in MDS, increased apoptosis is associated with ineffective progenitor and maturing hemopoietic cell survival, and occurs concomitant with cytopenias/ineffective hemopoiesis; conversely, the progression of MDS toward AML occurs in concert with decreased apoptosis and an increased degree of neoplastic cell survival, leading to subsequent expansion of the abnormal precursor cells. These processes are associated with alterations in the balance between pro- and anti-apoptotic oncoprotein expression within the hemopoietic precursors, which may be modified by cytokine treatment. Investigations evaluating apoptotic events in MDS have improved our understanding of the biology of hemopoietic cell survival as related to pathogenetic features of this disease. By modifying levels of apoptosis, such studies provide a framework for future potentially beneficial therapeutic approaches to treat patients with MDS.
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PMID:Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment. 1063 70

Hematological malignancies and premalignant diseases are generally of monoclonal origin. The prognostic and therapeutic significance of finding two genetically independent clones remains to be determined. We followed a case of childhood myelodysplastic syndrome showing biclonal chromosomal abnormalities (+8, -7) by conventional cytogenetic examination and double target fluorescence in situ hybridization (FISH). A 7-year-old girl presented with Plaut-Vincent angina and leukopenia. The cytogenetic aberration of +8 was the first sign to suggest MDS. Serial bone marrow controls, prompted by a progressive clinical course detected myelodysplastic changes and a new clonal aberration (-7). The presence of -7 and +8 in two independent clones was verified by double-target FISH. While at diagnosis and during cytokine treatment more cells showed +8, after successful all-trans retinoic acid (ATRA) therapy, the clone with -7 predominated. Following allogeneic bone marrow transplantation the patient displayed donor-derived hematopoesis. Our data stress the significance of cytogenetic and FISH examinations in detecting specific genetic abnormalities and progressive clonal changes as an indicator and guideline for therapy. Different cell clones characterized by different genetic changes might be associated with different biologic features reflected in their response to treatment.
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PMID:Biclonal chromosomal aberrations in a child with myelodysplastic syndrome. 997 18

Spontaneous intramedullary apoptosis was measured in bone marrow (BM) biopsies of 175 patients with myelodysplastic syndromes (MDS) using in situ end-labeling (ISEL) of fragmented DNA. Two groups of high (n=71) versus low (n =43) levels of apoptosis were identified while 61 patients were ISEL-negative. Semiquantitative assessment of 3 cytokines, the number of macrophages and in vivo labeling indices (LI) were also determined from consecutive sections of the biopsy. Patients with high apoptosis levels tended to have a high LI (p=0.013), more macrophages in their BM biopsies (p=0.006) and higher tumor necrosis factor alpha (TNF-alpha) levels (not significant) compared to patients with no apoptosis. In addition, low risk MDS patients had significantly lower rates of apoptosis (p = 0.047) and lower levels of TNF-alpha (p = 0.055) compared to high-risk MDS patients. We conclude that the genesis of cytopenias in MDS is of multifactorial origin and that cytokine-associated apoptosis clearly identifies a distinct biological subgroup of patients who may benefit selectively by use of anti-cytokine therapies.
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PMID:Biological characteristics of myelodysplastic syndrome patients who demonstrated high versus no intramedullary apoptosis. 1005 11

Normal somatic cells undergo replicative senescence in vitro but the significance of this process in organismic aging remains controversial. We have shown previously that hemopoietic stem cells of common inbred strains of mice vary widely in cycling activity and that this parameter is inversely correlated with strain-dependent mean life span. To assess whether cell cycling and life span are causally related, we searched for quantitative trait loci (QTLs) that contributed to variation of these traits in BXH and BXD recombinant inbred mice. Two QTLs, mapping to exactly the same intervals on chromosomes 7 and 11, were identified that were associated with variation of both cell cycling and life span. The locus on chromosome 11 mapped to the cytokine cluster, a segment that shows synteny with human chromosome 5q, in which deletions are strongly associated with myelodysplastic syndrome. These data indicate that steady-state cell turn-over, here measured in hemopoietic progenitor cells, may have a significant effect on the mean life span of mammals.
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PMID:Genetic analysis of hemopoietic cell cycling in mice suggests its involvement in organismal life span. 1009 31


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