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)

We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.
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PMID:Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. 1688 11

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

In vitro and in vivo, myeloid leukemic and preleukemic cells exhibit variable sensitivity to the antiproliferative and proapoptotic effects induced already at low concentrations of DNA methyltransferase (DNMT) inhibitors. The molecular mechanisms underlying this variable sensitivity of leukemic blasts to azanucleosides such as 5-azacytidine and 5-aza-2'-deoxycytidine (DAC) may involve modifier effects of specific fusion proteins such as AML1/ETO. The cyclin-dependent kinase inhibitor p15/INK4b is one potential target of DNA demethylating activity in AML and MDS where it is frequently silenced by hypermethylation. To study sensitivity to DAC in myeloid leukemia cells, we chose the myeloid cell lines Kasumi-1 (expressing AML1/ETO), KG-1 and KG-1a (both AML1/ETO-negative) all of which a highly methylated p15/INK4b gene. Treatment with DAC resulted in dose-dependent regional demethylation of p15/INK4b in Kasumi-1 and KG-1, but only to a modest degree in KG-1a cells. Demethylation was associated with induction of p15/INK4b protein expression. Growth-inhibitory and proapoptotic activity of DAC was significantly higher in Kasumi-1 than in KG-1a cells, and sensitization of cells to a cooperating effect of All-trans retinoic acid and of the histone deacetylase (HDAC) inhibitor Trichostatin A was observed. DAC-induced growth inhibition and apoptosis were enhanced when AML1/ETO was conditionally expressed in AML1/ETO-negative U-937 cells. In conclusion, hypomethylation and reactivation of p15/INK4b in myeloid cell lines are among the molecular events associated with DAC-induced growth arrest and apoptosis. Further studies of AML1/ETO as a modifier of the epigenotype and sensitivity of myeloid cells to inhibitors of DNMTs and HDACs appear warranted.
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PMID:Reversal of p15/INK4b hypermethylation in AML1/ETO-positive and -negative myeloid leukemia cell lines. 1705 12

Differential methylation of CpG islands is a regulatory mechanism for promoter activity of different classes of genes, including tissue-specific genes. These CpG islands are targets for transformation-associated, aberrant hypermethylation activity during leukemogenesis. Therefore the pharmacological reversion of this methylator phenotype (e.g. by reactivation of tumor suppressor gene expression) is an important rationale for development of inhibitors of DNA methyltransferase activity. In vitro, inhibition of methylation using azanucleosides results in modest differentiation of transformed myeloid cell lines. In vivo, low doses of these agents induce DNA demethylation of malignant myeloid cells. Indeed, the first drug specifically approved for the treatment of myelodysplastic syndrome (MDS) was the azanucleoside 5-azacytidine (Vidaza). The most potent DNA demethylating agent available, 5-aza-2' deoxycytidine (Decitabine, Dacogen) also has recently been approved by the U.S.A. FDA for treatment of MDS of all subtypes. About 30 % of MDS patients with an abnormal karyotype have normalization of their karyotype after receiving the drug. This activity is especially relevant in patients with high-risk karyotypic abnormalities (complex karyotype and/or abnormalities of chromosome 7) compared to patients with intermediate-risk karyotype. Both drugs offer a novel, non-intensive therapeutic approach, particularly in the older patient population who due to comorbidities and/or reduced performance status are ineligible for aggressive chemotherapies. Target genes being particularly prone to demethylation by these drugs in the aberrant cells (e.g. p15/INK4b) are under active investigation. Future translational and clinical studies will be aimed at improving the response rate and duration of response to non-intensive treatment with demethylating agents, by studying rational drug combinations e.g. with inhibitors of histone deacetylase activity.
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PMID:DNA hypermethylation of myeloid cells, a novel therapeutic target in MDS and AML. 1707 47

The t(7;11)(p15;p15) translocation, observed in acute myelogenous leukemia and myelodysplastic syndrome, generates a chimeric gene where the 5' portion of the sequence encoding the human nucleoporin NUP98 protein is fused to the 3' region of HOXA9. Here, we show that retroviral-mediated enforced expression of the NUP98-HOXA9 fusion protein in cord blood-derived CD34(+) cells confers a proliferative advantage in both cytokine-stimulated suspension cultures and stromal coculture. This advantage is reflected in the selective expansion of hematopoietic stem cells as measured in vitro by cobblestone area-forming cell assays and in vivo by competitive repopulation of nonobese diabetic/severe combined immunodeficient mice. NUP98-HOXA9 expression inhibited erythroid progenitor differentiation and delayed neutrophil maturation in transduced progenitors but strongly enhanced their serial replating efficiency. Analysis of the transcriptosome of transduced cells revealed up-regulation of several homeobox genes of the A and B cluster as well as of Meis1 and Pim-1 and down-modulation of globin genes and of CAAT/enhancer binding protein alpha. The latter gene, when coexpressed with NUP98-HOXA9, reversed the enhanced proliferation of transduced CD34(+) cells. Unlike HOXA9, the NUP98-HOXA9 fusion was protected from ubiquitination mediated by Cullin-4A and subsequent proteasome-dependent degradation. The resulting protein stabilization may contribute to the leukemogenic activity of the fusion protein.
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PMID:Enforced expression of NUP98-HOXA9 in human CD34(+) cells enhances stem cell proliferation. 1717 74

In bone marrow cells of 33 patients with myelodysplastic syndrome and acute myeloid leukemia, structural rearrangements of chromosome 7 were found with conventional G-banding: 8 with deletions 7q and 25 with translocations. In 29 of the patients, complex karyotypes were confirmed using multicolor fluorescence in situ hybridization (mFISH). Commercial probes (Abbot Molecular) were used for 7q22, 7q31, and 7q35, the regions most frequently deleted in myeloid malignancies. In three cases without deletions, high-resolution multicolor banding (mBAND) for chromosome 7 revealed other aberrations. Five groups of chromosomal rearrangements were established: (a) deletion 7q as a sole aberration (2 cases), (b) deletion 7q and complex karyotypes (6 cases), (c) combined translocations and deletions of 7q (17 cases), (d) combined translocation and deletion 7p (5 cases), and (e) translocation of chromosomes 7 without deletion 7p or 7q (3 cases). Deletions of all three FISH-screened regions were the most frequent, with heterogeneous breakpoints. The region 7p13.2 approximately p15.2 was most commonly deleted. Most of the deletions were cryptic, not detectable with conventional cytogenetics. Aberrations of chromosome 7 are associated with a very poor outcome; survival time in our cohort was short (median 7 months).
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PMID:Structural aberrations of chromosome 7 revealed by a combination of molecular cytogenetic techniques in myeloid malignancies. 1728 64

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

Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations. NUP98-HOXA9 is associated with the t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98-HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7-8 months. Transduction of NUP98 fusion genes into human CD34(+) cells confers a proliferative advantage in long-term cytokine-stimulated and stromal cocultures and in NOD-SCID engrafted mice, associated with a five- to eight-fold increase in hematopoietic stem cells. NUP98-HOXA9 expression inhibited erythroid and myeloid differentiation but enhanced serial progenitor replating. NUP98-HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim-1, and downmodulated globin genes and C/EBPalpha. The HOXA9 component of the NUP98-HOXA9 fusion protein was protected from cullin-4A-mediated ubiquitination and subsequent proteasome-dependent degradation. In NUP98-HOX-transduced CD34(+) cells and cells from AML patients with t(7;11)(p15;p15) NUP98 was no longer associated with the nuclear pore complex but formed intranuclear aggregation bodies. Analysis of NUP98 allelic expression in AML and myelodysplastic syndrome showed loss of heterozygosity observed in 29% of the former and 8% of the latter. This was associated with poor prognosis.
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PMID:NUP98 dysregulation in myeloid leukemogenesis. 1744 73

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

The t(2;11)(q31;p15) chromosomal translocation results in a fusion between the NUP98 and HOXD13 genes and has been observed in patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia. We previously showed that expression of the NUP98-HOXD13 (NHD13) fusion gene in transgenic mice results in an invariably fatal MDS; approximately one third of mice die due to complications of severe pancytopenia, and about two thirds progress to a fatal acute leukemia. In the present study, we used retroviral insertional mutagenesis to identify genes that might collaborate with NHD13 as the MDS transformed to an acute leukemia. Newborn NHD13 transgenic mice and littermate controls were infected with the MOL4070LTR retrovirus. The onset of leukemia was accelerated, suggesting a synergistic effect between the NHD13 transgene and the genes neighboring retroviral insertion events. We identified numerous common insertion sites located near protein-coding genes and confirmed dysregulation of a subset of these by expression analyses. Among these genes were Meis1, a known collaborator of HOX and NUP98-HOX fusion genes, and Mn1, a transcriptional coactivator involved in human leukemia through fusion with the TEL gene. Other putative collaborators included Gata2, Erg, and Epor. Of note, we identified a common insertion site that was >100 kb from the nearest coding gene, but within 20 kb of the miR29a/miR29b1 microRNA locus. Both of these miRNA were up-regulated, demonstrating that retroviral insertional mutagenesis can target miRNA loci as well as protein-coding loci. Our data provide new insights into NHD13-mediated leukemogenesis as well as retroviral insertional mutagenesis mechanisms.
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PMID:Retroviral insertional mutagenesis identifies genes that collaborate with NUP98-HOXD13 during leukemic transformation. 1754 93


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