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 involvement of 11q23-balanced translocations in acute leukemia after treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) is being recognized with increasing frequency. We and others have shown that the gene at 11q23 that is involved in all of these treatment-related leukemias is MLL (also called ALL1, Htrx, and HRX). In general, the translocations in these leukemias are the same as those occurring in de novo leukemia [eg, t(9;11), t(11;19), and t(4;11)], with the treatment-related leukemias accounting for no more than 5% to 10% of any particular translocation type. We have cloned the t(11;16)(q23;p13.3) and have shown that it involves MLL and CBP (CREB binding protein). The CBP gene was recently identified as a partner gene in the t(8;16) that occurs in acute myelomonocytic leukemia (AML-M4) de novo and rarely in treatment-related acute myeloid leukemia. We have studied eight t(11;16) patients, all of whom had prior therapy with drugs targetting topo II with fluorescence in situ hybridization (FISH) using a probe for MLL and a cosmid contig covering the CBP gene. Both probes were split in all eight patients and the two derivative (der) chromosomes were each labeled with both probes. Use of an approximately 100-kb PAC located at the breakpoint of chromosome 16 from one patient revealed some variability in the breakpoint because it was on the der(16) in three patients, on the der(11) in another, and split in four others. We assume that the critical fusion gene is 5'MLL/3'CBP. Our series of patients is unusual because three of them presented with a myelodysplastic syndrome (MDS) most similar to chronic myelomonocytic leukemia (CMMoL) and one other had dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or with t-AML. Using FISH and these same probes to analyze the lineage of bone marrow cells from one patient with CMMoL, we showed that all the mature monocytes contained the fusion genes as did some of the granulocytes and erythroblasts; none of the lymphocytes contained the fusion gene. The function of MLL is not well understood, but many domains could target the MLL protein to particular chromatin complexes. CBP is an adapter protein that is involved in regulating transcription. It is also involved in histone acetylation, which is thought to contribute to an increased level of gene expression. The fusion gene could alter the CBP protein such that it is constitutively active; alternatively, it could modify the chromatin-association functions of MLL.
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PMID:All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. 922 52

The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.
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PMID:MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). 923 46

Gene CBP codes for a transcriptional coactivator, which can interact with many transcriptional factors. It modifies the process of transcription stimulated by these factors by specific binding to RNA polymerase II holoenzyme or by histone acetylation. CBP gene mutation is the molecular cause of autosomal dominant genetic disease called Rubinstein-Taybi syndrome that is manifested by mental and growth retardations, by typical face malformations and broad thumbs and broad big toes. The CBP gene can be affected by the t(8;16)(p11;p13.3) translocation resulting in production of the MOZ/CBP chimeric protein and in induction of acute myeloblastic leukaemia. Therapy using topoisomerase II inhibitors can induce the t(11;16)(q23;13.3) translocation causing acute myeloid or lymphoid leukaemia or myelodysplasia through production of the MLL/CBP protein chimera.
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PMID:[Clinical sequelae of mutation of the CBP gene]. 1074 38

To date, seven different human histone deacetylases (HDACs) have been identified, which fall into two distinct classes. We have isolated and characterized a cDNA encoding a novel human HDAC, which we name HDAC8. HDAC8 shows a high degree of sequence similarity to HDAC1 and HDAC2 and thus belongs to the class I of HDACs. HDAC8 is expressed in a variety of tissues. Human cells overexpressing HDAC8 localize the protein in sub-nuclear compartments whereas HDAC1 shows an even nuclear distribution. In addition, the HDAC8 gene is localized on the X chromosome at position q13, which is close to the XIST gene and chromosomal breakpoints associated with preleukemia.
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PMID:Cloning and characterization of human histone deacetylase 8. 1092 73

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

In this study, we examined a pediatric case of therapy-related myelodysplastic syndrome (tMDS). The symptoms developed 17 months after treatment for acute myeloblastic leukemia (AML, M2 subtype according to the French-American-British [FAB] classification) involving a chromosome abnormality at t(8;21)(q22;q22). Upon diagnosis of tMDS, spectral karyotyping analysis detected a new chromosomal translocation at t(2;8)(p23;p11.2). In addition, fluorescence in situ hybridization analysis suggested a rearrangement in the monocytic leukemia zinc finger (MOZ) gene, located in the 8p11 region of chromosome 8. However, no partner gene on 2p23 could be identified. To our knowledge, this is the first report of tMDS associated with a rearrangement of the MOZ gene. MOZ-linked fusion proteins such as MOZ-CBP (CREB binding protein), MOZ-TIF2 (transcriptional intermediary factor 2), and MOZ-p300 (adenoviral E1A-associated protein) are associated with AML chromosomal abnormalities at t(8;16)(p11;p13), inv(8)(p11q13), and t(8;22)(p11;q13), respectively, and are thought to account for leukemogenesis occurring through the aberrant regulation of histone acetylation. Through a similar mechanism, we believe that MOZ, fused to an unidentified partner gene at 2p23, may have caused an alteration in histone acetylation, resulting in the development of tMDS in this patient.
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PMID:Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11). 1261 66

DNA methylation is an epigenetic phenomenon influencing the normal function of DNA and its scaffolding proteins. Especially in cancer, aberrant methylation patterns may contribute to the disease process by the induction of point mutations, activation of inactive genes through hypomethylation of promoters, and transcriptional inactivation through a complex interplay with histone acetylation and other inhibitory mechanisms. Aberrant methylation patterns have been evaluated as tools in the management of patients with cancer. The predictive value, the therapeutic manipulation and the prognostic significance of aberrantly methylated gene loci have been tested in hematological as well as in solid neoplasias in adults and children. A seemingly insurmountable wealth of data has been generated, however, data on clinical associations are sometimes presented in an almost incautious fashion. Nevertheless, some genes like p15INK4B in myelodysplastic syndrome (MDS) and p16INK4A in some lung cancer subtypes have been shown to confer a certain prognosis. In selected cases the data have been confirmed by independent studies. Assays have been developed that can be used by almost any clinical laboratory (e.g. methylation-specific PCR) for the rapid and affordable screening of tumors for aberrant methylation. The study of aberrant methylation patterns has successfully entered the arena of relevant clinical applications. Importantly, methylation does not only hold the potential for being 'just another' biomarker, but also, as it can be reverted chemically, it is a phenomenon that holds great promise for therapeutic exploitation.
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PMID:DNA methylation patterns in cancer: novel prognostic indicators? 1293 Jan 58

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

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

Myelodysplastic syndrome is characterized by ineffective hematopoiesis manifesting as peripheral cytopenia, despite adequate or increased cellularity in bone marrow. Increased intramedullary apoptosis is thought to be the mechanism underlying this phenomenon. However, the mechanisms leading to this increased apoptosis remain largely unknown. Although less apoptosis is seen in more advanced disease with increased blasts, apoptosis remains the major characteristic feature of this disease and data suggest that all cases are biologically similar, irrespective of the blast count. Myelodysplastic syndrome is a highly aggressive disease that carries a poor prognosis, especially in symptomatic patients. New therapeutic agents that target histone deacetylation, DNA methylation, or angiogenesis show promise, but focused biologic and therapeutic studies are needed to improve the outcome of this disease.
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PMID:Myelodysplastic syndrome: from morphology to biology. 1508 62


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