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)

Hexamethylene bisacetamide (HMBA) is referred as a differentiation-inducer for the clinical treatment of acute myeloid leukemia and myelodysplastic syndrome. However, the molecular mechanism of the effects of HMBA on myeloid leukemic cells remains unknown. In this study, the effects of HMBA on cell cycle and expression of cell cycle regulatory proteins in HL-60 cell were investigated in order to explore its pharmacological mechanism. The altered distribution of cell cycle and expression of its regulatory proteins (cyclin D, cyclin E and p27) in HL-6 0 cell induced by HMBA were analyzed by flow cytometry. The effects on transcription for mRNA of CKI p15, p16 and p27 in HL-60 cell were further studied by RT-PCR. The results showed that HMBA could mainly commit HL-60 cell to G0/G1 arrest and the significantly decreased endocytic cyclin E protein and increased cyclin D/p27 protein after HMBA treatment were found. There was no expression of p15, p16 mRNA in untreated HL-60 cell and 3 mmol/L of HMBA could make them expressed after exposed for 24 h or 48 h respectively. The expression of p27 mRNA was positive and no obviously different in untreated HL-60 cells exposed for 24 h, 48 h and 72 h. These results suggested that one of the pharmacological mechanisms of HMBA was to elevate the expression of p27 and reduce the cyclin E expression as well as to activate the expression of p15, p16 gene mRNA, that arrested cell at G0/G1 and exerted its effects of anti-proliferation.
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PMID:[Effects of hexamethylene bisacetamide on cell cycle and expression of its regulatory proteins in HL-60 cells]. 1457 41

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

Aberrant DNA methylation is frequently observed in adults with myelodysplastic syndrome (MDS), and is recognized as a critical event in the disease's pathogenesis and progression. This is the first report to investigate the methylation status of p15 and p16, cell cycle regulatory genes, in children with MDS (n = 9) and juvenile myelomonocytic leukaemia (JMML; n = 18) by using a methylation-specific polymerase chain reaction. The frequency of p15 hypermethylation in paediatric MDS was 78% (7/9), which was comparable to that in adult MDS. In contrast, p15 hypermethylation in JMML was a rare event (17%; 3/18). In JMML, clinical and laboratory characteristics including PTPN11 mutations and aberrant colony formation were not different between the three patients with hypermethylated p15 and the others. Aberrant methylation of p16 was not detected in children with either MDS or JMML. Since p15 and p16 genes were unmethylated in two children with JMML, in whom the disease had progressed with an increased number of blasts, a condition referred to as blastic crisis, we infer that the aberrant methylation of these genes is not responsible for the progression of JMML. The results suggest that demethylating agents may be effective in most children with MDS and a few patients with JMML.
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PMID:Methylation status of the p15 and p16 genes in paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia. 1575 84

We determined bone marrow karyotype at diagnosis in four female acute myeloid leukemia (AML) or myelodysplasia patients, aged between 52 and 56 years. In each case, we observed chromosome rearrangement involving the same 4q24 band. Three patients had a balanced reciprocal translocation as the sole abnormality - t(3;4)(q26;q24), t(4;5)(q24;p16) and t(4;7)(q24;q21) - and the fourth had del(4)(q23q24), +4. We used a set of 4q BAC probes for fluorescent in situ hybridization (FISH) in these four cases. We found a 4q24 submicroscopic deletion in all three translocations, with a common deletion of approximately 0.5 Mb. In three cases, we concluded that rearrangement occurred in an early hematopoietic stem cell, as it was detected, in mosaic with a normal karyotype, in a fraction of remission bone marrow cells, peripheral T and B lymphocytes, malignant lymph node T-lymphoma cells in one case and B-lymphoblastoid cell lines established in two cases. Moreover, one of 10 additional AML patients tested by FISH had a normal karyotype and deletion of one of the commonly deleted probe sequences. A tumor suppressor gene may therefore be involved, especially as two patients developed malignant lymphoma at the same time as myeloid proliferation.
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PMID:Common 4q24 deletion in four cases of hematopoietic malignancy: early stem cell involvement? 1592 Apr 87

Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic disorders characterized by dyshemopoiesis and frequent evolution to acute leukemia. Tumor suppressor gene inactivation may be involved in MDS pathogenesis. The two families of cyclin-dependent kinase inhibitors (CDKIs) (INK4 family of p15, p16, p18 and p19 and CIP/KIP family of p21, p27 and p57) that negatively regulate cell cycle progression are known tumor suppressor genes. To determine whether genetic alterations of p16 and p27 genes play an important role in MDS pathogenesis, we examined DNA from 51 patients classified as 17 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 19 refractory anemias with an excess of blasts (RAEB), 5 refractory anemias with excess of blasts in transformation (RAEB-t) and 6 chronic myelomonocytic leukemias (CMML). Southern blot analysis detected no homozygous deletions of p16 and p27. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing did not reveal point mutations for both genes with the exception of two allelic polymorphisms, namely a C --> G transition at 447 bp of p16exon3 and a T --> A transition at 791 bp of p27exon1 genes. Our results suggest that mutations of p16 and p27 genes resulting in abnormal p16 and p27 proteins do not represent a mechanism of gene inactivation involved in the pathogenesis of MDS.
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PMID:Absence of p16 and p27 gene rearrangements and mutations in de novo myelodysplastic syndromes. 1610 74

Hypermethylation of CpG islands within the promoter region is one of the mechanisms by which genes are inactivated and may be one of the reason for silencing of cell cycle control or DNA-mismatch repair genes in myelodysplastic syndrome (MDS). Since the function of cell cycle control genes including the cyclin-dependent kinase inhibitors known as p15(INK4b) and p16(INK4a), as well as p14(ARF) which blocks MDM-2 (an inhibitor of p53), the retinoblastoma (RB1) protein and the mismatch repair gene MGMT is critical for hematopoietic proliferation and differentiation, we performed methylation specific polymerase chain reaction (MSP) in low-density, non-adherent bone marrow cells from 49 patients with MDS. In addition, expression of p15(INK4b) and RB1 was analysed by quantitative real-time PCR. From selected patients, we analyzed the methylation pattern of cell cycle control genes in CD34+ bone marrow cells. Thirty-nine of 49 cases (80%) had at least one of five genes methylated in our MDS samples by analysing low-density non-adherent bone marrow cells. The frequency of p15(INK4b) methylation was 34 of 49 samples (69%). The incidence of methylation of both p14(ARF) and p16(INK4a) was four of 49 (8%). RB1 gene was methylated in seven samples (14%) and each patient had RA. Interestingly, none of these genes were methylated in the purified CD34+ hematopoietic stem cells from the MDS patients. Furthermore, all our RARS patients had a methylated p15(INK4b) promoter correlating with non-detectable expression of this gene in bone marrow cells from those patients. These results indicate that hypermethylation of cell cycle control genes in MDS may occur late during the differentiation of myelodysplastic stem cells.
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PMID:Comparative analysis of hypermethylation of cell cycle control and DNA-mismatch repair genes in low-density and CD34+ bone marrow cells from patients with myelodysplastic syndrome. 1668 76

Transcriptional silencing of tumor suppressor genes, associated with DNA methylation, is a common epigenetic event in hematologic malignancies. Although DNA hypermethylation of CpG islands is well described in acute leukemias and myelodysplastic syndromes, much less is known of the specific methylation changes that commonly occur in follicular B cell lymphomas. Earlier methylation studies of follicular lymphoma involved only cell lines; however there is a growing literature of methylation changes in primary human FL samples. Published studies of primary follicular lymphoma specimens have demonstrated that: androgen receptor, SHP1, and death-associated protein kinase genes are commonly methylated. By contrast, the cyclin dependent kinase inhibitors p15, p16, and p57 are uncommon epigenetic events in follicular lymphoma. Methylation of cyclin dependent kinase inhibitors is more common in high grade lymphomas, and may be an important step in the progression and transformation of follicular lymphoma. Further methylation studies in follicular lymphoma should investigate the prognostic and therapeutic significance of these epigenetic changes and investigate methylation of other genes. Finally, reactivation of methylated tumor suppressor genes through the use of hypomethylating agents is a promising and novel approach to the treatment of indolent and transformed follicular lymphomas.
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PMID:Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review. 1702 65

We report on characteristics of the first human cell line, PC-MDS, derived from a bone marrow of a patient with therapy-related myelodysplastic syndrome (t-MDS) who had no overt post-MDS leukemia. Classic cytology analyses, immunophenotyping, cytogenetic and molecular genetic procedures were used for characterization of the cell line. PC-MDS cells are positive for the expression of CD13, CD15, CD30, CD33, and CD45 antigen. Positive cytochemical staining and immunophenotype analyses indicated that PC-MDS cells have some characteristics of the early myeloid precursor cell. The karyotype analysis of PC-MDS cell line revealed various numerical and structural changes including those typically associated with t-MDS: del(5)(q13)[7], der(5)t(5;11)(p11;q11)[13], -7[6], del(7)(q31)[2], +20[3], -20[4]. Evaluation of methylation status in a promoter region of p15, p16 and MGMT genes showed biallelic hypermethylation pattern of 5' promoter region only in MGMT gene. PC-MDS is the first t-MDS derived cell line, and based on its immunological, cytogenetic and molecular characterization could be a new tool in evaluation of complex biology of MDS and a model for methylation studies.
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PMID:Characteristics of novel myeloid precursor cell line, PC-MDS, established from a bone marrow of the patient with therapy-related myelodysplastic syndrome. 1735 Jun 82

The past decade has seen an explosion of interest in the epigenetics of cancer, with an increasing understanding that this form of genomic modification plays a critical role in pathogenesis. The malignant phenotype results from a step-wise increase of both genetic abnormalities and epigenetic modifications, leading to dysregulation of critical genes controlling cell growth, differentiation and apoptosis. The methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism that is frequently dysregulated in human cancer. This phenomenon (methylation of CpG islands) plays a critical role in the transcriptional silencing of tumour suppressor genes in cancer and has prompted the development and testing of several demethylating agents aimed at reversing this process. Clinical trials using epigenetically targeted therapies have yielded particularly promising results in the myelodysplastic syndromes (MDS), in which tumour suppressor gene silencing by promoter methylation is a frequent event. Several genes and gene pathways disrupted by aberrant CpG island methylation have now been identified in haematological malignancies, the most frequently studied being the cell cycle inhibitors p16 (now termed CDKN2A; mostly methylated in lymphoid malignancy) and p15 (now termed CDKN2B; commonly methylated in lymphoid and myeloid malignancies). This review will discuss the role that aberrant gene silencing by promoter hypermethylation plays in the molecular pathogenesis of haematological malignancies and assess the clinical potential of demethylating agents for the management of patients.
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PMID:Gene silencing by DNA methylation in haematological malignancies. 1748 80

Deregulated epigenetic mechanisms are likely involved in the pathogenesis of myelodysplastic syndromes (MDSs). Which genes are silenced by aberrant promotor methylation during MDS hematopoiesis has not been equivalently investigated. Using an in vitro differentiation model of human hematopoiesis, we generated defined differentiation stages (day 0, day 4, day 7, day 11) of erythro-, thrombo- and granulopoiesis from 13 MDS patients and seven healthy donors. Promotor methylation analysis of key regulatory genes involved in cell cycle control (p14, p15, p16, CHK2), DNA repair (hMLH1), apoptosis (p73, survivin, DAPK), and differentiation (RARb, WT1) was performed by methylation-specific polymerase chain reaction. Corresponding gene expression was analyzed by microarray (Affymetrix, HG-U133A). We provide evidence that p16, survivin, CHK2, and WT1 are affected by promotor hypermethylation in MDSs displaying a selective International Prognostic Scoring System risk association. A methylation-associated mRNA downregulation for specific hematopoietic lineages and differentiation stages is demonstrated for survivin, CHK2, and WT1. We identified a suppressed survivin mRNA expression in methylated samples during erythropoiesis, whereas WT1 and CHK2 methylation-related reduction of mRNA expression was found during granulopoiesis in all MDS risk types. Our data suggest that lineage-specific methylation-associated gene silencing of survivin, CHK2, and WT1 in MDS hematopoietic precursor cells may contribute to the MDS-specific phenotype
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PMID:DNA methylation profiling of myelodysplastic syndrome hematopoietic progenitor cells during in vitro lineage-specific differentiation. 1757 21


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