UMLS:C0026986 - FACTA Search

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

The recurrent translocation t(11;16)(q23;p13) has been reported to be associated with therapy-related acute leukemia. The MLL gene involved in other 11q23 abnormalities was also rearranged by this translocation. We analyzed two patients with myelodysplastic syndrome with t(11;16) and showed that the MLL gene on 11q23 was fused with CREB-binding protein (CBP) gene on 16p13 in these patients. The CBP gene encodes a transcriptional adaptor/coactivator protein and it is mutated in patients with Rubinstein-Taybi syndrome. The CBP gene is also involved in acute myeloid leukemia (AML) with t(8;16)(p11;p13). In-frame MLL-CBP fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with a largely intact CBP. Our results combined with the finding of the MOZ-CBP fusion in t(8;16)-AML suggest that the CBP gene may be associated with leukemogenesis through translocations.
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PMID:The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. 916 31

The therapeutic dilemma that confronts the management of patients with myelodysplastic syndromes (MDS) is illustrated by the absence of a Food and Drug Administration-approved agent with an indication for this disease. Clinical heterogeneity and inadequate understanding of the disease pathobiology have limited progress in the development of novel therapeutics. Preclinical investigations indicate that reciprocal interaction between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptotic loss of progenitors and their progeny. Evidence to support this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis factor-alpha concentration and DNA oxidation and glutathione depletion in malignant CD34+ progenitors. Recent investigations indicate that angiogenic molecules generated by malignant myelomonocytic precursors represent integral diffusable signals that reinforce leukemia progenitor self-renewal while promoting the generation of proapoptotic cytokines and medullary angiogenic response. The potential for leukemia evolution is compounded by epigenetic events including methylation silencing of the p15 proto-oncogene or activating ras point mutations. Delineation of such biologic features that are central to the pathobiology of MDS provides a reliable framework for the development of novel therapeutics. Antiangiogenic agents in clinical testing include vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, thalidomide and related analogues, and the recombinant VEGF neutralizing antibody, bevacizumab. Agents whose actions may restore differentiation programs, such as the DNA methyltransferase inhibitors or histone deacetylase inhibitors, offer the prospect to promote effective hematopoiesis while impacting the potential for leukemia evolution. RAS farnesyl transferase inhibitors have shown encouraging preliminary results in acute myeloid leukemia and are currently under investigation in advanced MDS and chronic myelomonocytic leukemia. Arsenic trioxide (ATO) interacts with a spectrum of biologic targets that may be uniquely suited to MDS. ATO is a potent inducer of apoptosis in thiol-depleted malignant progenitors and neovascular endothelium, while promoting differentiation through histone acetylation and inactivation of transcriptional corepressors. The identification of relevant biologic targets in MDS has raised expectations for the development of disease-specific therapies for MDS in the years that follow.
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PMID:New approaches to the treatment of myelodysplasia. 1196 Dec 8

The important cell cycle regulatory gene p15(INK4b) has been shown to be inactivated in acute myeloid leukemia and myelodysplastic syndrome. Little is known about the expression and epigenetic modification of this gene in chronic myelomonocytic leukemia (CMML) that belongs to the myelodysplastic/myeloproliferative disorders (MDS/MPD) with a high proportion of blastic transformation. Analysis of bone marrow trephines in a series of 33 CMML cases showed an aberrant p15(INK4b) gene methylation in up to 58% of cases. Methylation was analyzed employing different methylation-specific PCR and genomic sequencing protocols. It turned out to be spread over a broad area of the 5' region and exhibited substantial heterogeneity between cases and even in individual patients. The degree of aberrant methylation was correlated with a reduced mRNA as well as reduced protein expression, and was associated with a higher expression of DNA methyltransferase DNMT 3A. We conclude that aberrant gene methylation is a frequent event in CMML that might contribute to the pathogenesis of this MDS/MPD.
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PMID:Aberrant methylation and impaired expression of the p15(INK4b) cell cycle regulatory gene in chronic myelomonocytic leukemia (CMML). 1275 Jul 5

Frequent genetic alterations in hematopoietic neoplasias (chromosomal translocations, point mutations, etc.) have provided biologic targets for the development of effective novel therapies. A rapidly increasing body of knowledge provides evidence also for multiple epigenetic alterations in these disorders, which can complement or even precede genetic aberrations. Gene inactivation ('silencing') of tumor suppressor and growth inhibitory genes (e.g. the cyclin-dependent kinase inhibitors p16, p15, p21) is frequently mediated by DNA methylation of gene promoters. The acetylation state of histones (functionally linked to the DNA methylation state by the methylcytosine binding protein 2, recruiting histone deacetylases) provides a second major epigenetic silencing mechanism. Therapeutic reversal strategies are being developed for acute leukemias, myelodysplastic syndromes and malignant lymphomas. Since the discovery of the DNA methyltransferase (Dnmt) inhibitory activity of two azanucleosides (5-azacytidine, 5-aza-2'-deoxycytidine/decitabine) even at doses with minimal nonhematologic toxicity, both have been clinically studied in several myeloid neoplasias, particularly in elderly patients unable to tolerate aggressive treatment. Further development of agents counteracting aberrant methylation is directed at more targeted approaches, for example, antisense molecules against Dnmts. Histone deacetylases (HDACs) can be inhibited by numerous compounds (sodium phenylbutyrate, valproic acid, novel compounds such as depsipeptide), which have entered the clinical arena in similar indications as Dnmt inhibitors. Impressive effects of HDAC inhibition in acute promyelocytic leukemia models (PML/RARA expression) translate the finding of HDAC recruitment by this chimeric transcription factor to its target genes. The recent discovery of recruitment by PML/RARA also of Dnmt activity to the retinoic acid receptor-beta promoter makes it an interesting candidate for Dnmt inhibitors. Studies combining a 're-expressor' strategy with inhibitors of Dnmts and HDACs are underway. Thus, resensitization to biological agents such as retinoids, colony-stimulating factors and other differentiation inducers may be envisioned.
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PMID:Epigenetic targets in hematopoietic malignancies. 1452 73

DNA methylation abnormalities have recently emerged as one of the most frequent molecular changes in hematopoietic neoplasms. Since methylation and transcriptional status are inversely correlated, the hypermethylation of genes involved in cell-cycle control and apoptosis could have a pathogenetic role in the development of cancer. In particular, high-risk myelodysplastic syndromes (MDS) and secondary leukemias show a high prevalence of tumor suppressor gene hypermethylation. The progression of chronic myeloproliferative diseases and of myelodysplastic syndromes, as well as that of lymphoproliferative diseases, is associated with an increased methylation rate, pointing to a role for hypermethylation of critical promoter regions in the transformation to more aggressive phenotypes. In the same line, a significantly worse prognosis has been shown for patients with hypermethylation of several genes compared to that of patients with unmethylated genes. For these reasons, the use of irreversible DNA methyltransferase inhibitors, such as 5-azacytidine and Decitabine, appears to be a promising option for the treatment of MDS and acute myeloid leukemia. In clinical trials, Azacytidine results in a significantly higher response rate, improved quality of life, reduced risk of leukemic transformation, and improved survival compared to supportive care. Similarly, Decitabine showed favorable results, promising response rates, a good nonhematologic toxicity profile, and a trend for better survival compared to intensive chemotherapy, particularly in older patients. The synergistic effect of histone deacetylase inhibitors, including phenylbutyrate (PB), in reactivating silenced genes encouraged clinical studies on the combination of PB and demethylating agents in hematological diseases, characterized by p15 silencing. The sequential administration of a "first generation" demethylating agent and HDAC inhibitors gave preliminary evidence of a reduced methylation of target genes, as also described with Decitabine. Clinical trials are still ongoing, and preliminary data indicate for the first time that the natural history of MDS may be changed by a non-intensive treatment, characterized by an outstanding toxicity profile.
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PMID:Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. 1458 80

The last decade has witnessed a multistep evolution in the understanding of the natural history, clinical manifestations, and some of the molecular mechanisms that underlie the ineffective hematopoiesis and leukemic transformation in the myelodysplastic syndrome (MDS). The international prognostic scoring system, FAB, and WHO classifications have helped define specific subgroups with their characteristic cytogenetic, molecular and immunological abnormalities. Until recently the mainstay of the treatment has been entirely supportive with blood and platelet transfusions. What is increasingly manifest now is the considerable excitement generated by the emergence of novel therapeutic strategies based on painstaking research findings from the laboratories. In Section I, Dr. Alan List reviews the therapeutic strategies with the specific emphasis on the relevance of molecular mechanism of apoptosis and targeted therapies using small molecules. Of particular interest is the excitement surrounding the clinical benefit obtained from potent immunomodulatory derivative (IMiD) of thalidomide CC5013. The review provides an update of the role of small molecule inhibitors of VEGF receptor tyrosine kinase, arsenic trioxide, oral matrix metalloprotease inhibitors, farnesyl transferase inhibitors, and imatinib mesylate in the treatment of MDS subgroups. In Section II, Dr. Steven Gore describes the results of clinical trials of inhibitors of DNA methylation such as 5 azacytidine (5 AC) and 5-aza 2-deoxycytidine (Decitabine). The review also provides an update on the rationale and results obtained from the combination therapy using histone deacetylases (HDAC) and DNA methyltransferase inhibitors in the treatment of MDS. In Section III, Professor Ghulam Mufti and Dr. Aloysius Ho describe the role of bone marrow transplantation with particular emphasis on recent results from reduced-intensity conditioned transplants, exploiting the graft versus leukemia effect without significant early treatment-related mortality. The section provides an update on the results obtained from the manipulation of the host's immune system with immunosuppressive agents such as ALG and/or cyclosporine A.
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PMID:Myelodysplastic syndrome. 1463 82

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a 'hypermethylation profile' in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies. This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.
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PMID:DNA methylation in haematological malignancies: the role of decitabine. 1464 Sep 42

Myelodysplastic syndromes have long provided hematologists with difficult therapeutic challenges, and until recently treatment options beyond supportive care were limited. Recent advances in our understanding of hematopoiesis, immunology, and genetics have led to a better understanding of the natural history of these disorders and have facilitated development of more rational and targeted treatment approaches. A number of promising agents are in various phases of study, including arsenic trioxide, CC5013, the farnesyltransferase inhibitors, and DNA methyltransferase inhibitors. In addition, less intensive strategies for allogeneic stem cell transplantation now permit us to offer potentially curative therapy to a larger proportion of patients. Optimal management of an individual patient requires consideration of the disease and its expected course, available treatment options, the patient's age and condition, and an ongoing assessment of the goals of therapy.
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PMID:Update on myelodysplastic syndromes: new approaches to classification and therapy. 1512 38

To investigate the effect of 5-aza-2'-deoxycytidine (5-Aza-CdR) on cell of high-risk patients with myelodysplastic syndrome (MDS) in vitro, the growth inhibition of MUTZ-1 cell induced by 5-Aza-CdR was detected by MTT method; apoptosis was detected by morphological observation and translocation of phosphatidylserine (PS) was examined by flow cytometry assay; the expressions of P15INK4B, DNA methyltransferases (DNMT)(1), DNMT(3A) and DNMT(3B) gene on mRNA level were detected by RT-PCR; methylation of p15INK4B gene in MUTZ-1 cells was detected by PCR using methylation specific primer (MSP). The results showed that 5-Aza-CdR inhibited the growth of MUTZ-1 cells. The IC(50) values of 24, 48 and 72 hours were 6.75, 2.82 and 5.45 mmol/L respectively. Characteristic changes of apoptosis emerged in MUTZ-1 cells after being exposed to 5-Aza-CdR in the different concentration from 0.8 mmol/L to 3.2 mmol/L, and the positive cells of annexin V on the membrane of MUTZ-1 cells were analyzed by flow cytometry. 5-Aza-CdR could activate the p15INK4B gene expression in MUTZ-1 cells by demethylation of the p15INK4B gene in a dose-dependent manner after the cells were treated for 48 hours. Furthermore, 5-Aza-CdR could significantly down-regulate the expressions of DNA methyltransferase genes DNMT(3A) at mRNA level in a dose dependent manner. However, it had no effects on DNMT(1) gene and DNMT(3B) gene. It is concluded that 5-Aza-CdR can inhibit the growth of MUTZ-1 cells and induce the apoptosis of these cells within the range of concentration from 0.8 mmol/L to 3.2 mmol/L, which may be one of the mechanisms of antitumor effects of 5-Aza-CdR. The drug can activate the expression of p15INK4B gene in MUTZ-1 cells by demethylation of the p15INK4B gene through inhibiting the expression of DNMT(3A) gene. It may be the mechanism of 5-Aza-CdR in the treatments of MDS.
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PMID:[Effect of 5-aza-2'-deoxycytidine on cell of high-risk patients with myelodysplastic syndrome in vitro]. 1536 33

Myelodysplastic syndrome (MDS) is an acquired bone marrow disorder characterized by ineffective hematopoiesis and cellular dysfunction and has an increased risk of transforming into acute myeloid leukemia. Most patients are of advanced age with attendant comorbidities, making treatment difficult. Current treatment options have included supportive care and, in difficult cases, chemotherapy regimens designed for acute leukemia patients. A major effort has been made to determine the role of stem cell transplantation in adult MDS patients, currently the only curative option available for them. Based on relapse rates, studies indicate that allogeneic and autologous transplants provide better antileukemic activity than intensive chemotherapy schedules. Use of DNA methyltransferase inhibitors may assist in managing MDS patients while awaiting a transplant match, but the procedural mortality for transplant remains high. Reduced conditioning or nonmyeloablative conditioning, particularly in the elderly, has been attempted with some success. Reduced conditioning also increases the graft-versus-leukemia effect, allowing for a higher percentage of disease-free survival. Current use of peripheral blood as a source of stem cells for autotransplant is associated with an extremely low procedural mortality. Improvement in such transplant procedures as myeloablation, preparation of the autograft, and posttransplant prophylaxis are improving recovery rates for these patients. In addition, as the biology of this disease is being revealed, newer options will become available in the near future.
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PMID:Transplant strategies for myelodysplastic syndrome. 1549 94

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