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

Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP-CMML) and 22 cases of myelodysplastic forms (MD-CMML) using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP-CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients.
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PMID:ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. 2088 Jan 16

Frequent mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) have been identified in gliomas and acute myeloid leukemia (AML). Our aim is to assess whether IDH mutations were presented in Chinese patients with various hematological disorders. In this study, we screened the IDH1 and IDH2 mutations in a cohort of 456 Chinese patients with various hematological malignancies and disorders. We found three missense (p.R132C, p.R132G, and p.I99M; occurred in five patients) and one silent mutation (c.315C>T; occurred in two patients) in the IDH1 gene and two missense mutations (p.R140Q and p.R172K; occurred in four AML patients) and one silent mutation (c.435G>A) in the IDH2 gene. Except for one non-Hodgkin lymphoma (NHL) patient harboring IDH1 mutation p.R132C, all IDH1 and IDH2 missense mutations were observed in patients with AML. Intriguingly, the IDH2 mutation p.R140Q and novel IDH1 mutation p.I99M co-occurred in a 75-year-old patient with AML developed from myelodysplastic syndromes (MDS). The frequency of IDH1 and IDH2 missense mutations in Chinese AML patients reached 5.9% and 8.3%, respectively. Our results supported the recent findings that IDH gene mutations were common in AML. Conversely, IDH mutations were rather rare in Chinese patients with other types of hematological disorders.
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PMID:IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders. 2094 81

Myelodysplastic syndromes (MDS) are clonal hematologic neoplasms that can result in cytopenias and increase the risk of leukemic transformation. The disease is characterized by several recurrent cytogenetic defects, which can affect diagnosis, prognosis, and treatment. Metaphase cytogenetics (MC) is the gold standard in karyotypic analysis in hematology. Progress in molecular analysis, including additional karyotypic tools exemplified by fluorescence in situ hybridization, comparative genomic hybridization, and more importantly, single nucleotide polymorphism array (SNP-A) analysis, has led to increased detection of chromosomal abnormalities in myeloid malignancies and improved prognostic risk stratification. SNP-A, together with MC, has also been instrumental in the discovery of genes that have improved our understanding of the biology of MDS. Newly elucidated molecular abnormalities in MDS include mutations in CBL, TET2, ASXL1, IDH1/IDH2, EZH2, DNMT3A, and UTX. This review provides an update on the changing landscape of molecular and cytogenetic characterization in MDS and its significance in disease biology and clinical practice.
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PMID:Updates in cytogenetics and molecular markers in MDS. 2134 May 13

Myeloproliferative/myelodysplastic syndromes are rare diseases that include a proliferative component, mainly on the white cells and platelets, and a dysplastic component that accounts for one or several cytopenias. The most frequent of these diseases in chronic myelo-monocytic leukemia, a disease of elderly people that has long been associated with myelodysplastic syndromes in biological studies as well as in clinical trials. The recent identification of a number of genetic mutations in the leukemic clone, including frequent mutations in TET2, ASXL1 and RUNX1, less frequent mutations in NRAS, KRAS and C-CBL, and rare mutations in JAK2, FLT3, IDH1, IDH2, and EZHR2 may improve our understanding of the pathogenesis of this disease. Patient care depends on the disease risk, especially the percentage of blast cells in the bone marrow, the age and the performance status. Supportive care is required in all patients. In high risk patients, the only curative therapeutic is allogeneic hematopoietic stem cell transplantation, which is rarely feasible due to the age of the patients and the absence of donor. Demethylating agents such as azacitidine and decitabine are currently the most efficient drugs. The prognosis remains poor, with a median survival lower than 24 months.
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PMID:[Myeloproliferative/myelodysplastic syndromes]. 2142 42

In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors.
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PMID:Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy. 2181 4

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and a high propensity to transform to acute myeloid leukemia (AML). In the pathogenesis of the disease, both gene mutations and cytogenetic changes play an important role. The latter have been integrated into prognostic scoring systems including the IPSS (International Prognostic Scoring System) and WPSS (World Health Organization [WHO] classification-based Prognostic Scoring System). In these systems and in multivariate analyses comparing clinical and genetic data, complex karyotypes are associated with a particularly poor prognosis. del(5q) plays a distinct role by classifying the only genetically defined WHO subtype. Also, due to advancement in technology such as whole genome sequencing, the number of known mutations occurring in MDS is steadily increasing. Important recent discoveries include mutations in EZH2, DNMT3A, ASXL1 and IDH1/2. Like TET2, the most commonly mutated gene in MDS, all are involved in epigenetic regulation. Mutations such as ASXL1, RUNX1, EZH2, ETV6/TEL and TP53 have an adverse impact on patient overall survival. Early evidence suggests that some mutations might influence treatment response, necessitating reassessment of the prognostic effect of genetic alterations in the light of every new treatment. This review discusses clinical and biological effects of the most common cytogenetic and molecular aberrations in patients with MDS.
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PMID:Update on cytogenetic and molecular changes in myelodysplastic syndromes. 2187 99

The somatic mutations of isocitrate dehydrogenase genes (IDH1 and IDH2) have been identified in a proportion of hematologic malignancies. We examined IDH1 R132 and IDH2 R140/R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with different myeloid malignancies including 198 acute myeloid leukemia (AML), 82 myelodysplastic syndrome (MDS), 85 chronic myeloid leukemia, and 57 myeloproliferative neoplasms. IDH1 and IDH2 mutations were found in four (2.0%) and ten (5.0%) AML and in two (2.4%) and three (3.6%) MDS cases, but not in other patients. IDH1 and IDH2 mutations were heterozygous and mutually exclusive. IDH1/2 mutations were significantly more frequently observed in cytogenetically normal AML or MDS compared to those without mutations. There was no difference in overall survival of both AML and MDS patients with or without IDH1/2 mutations (P = 0.177 and 0.407, respectively). In conclusion, IDH1/2 mutations are recurrent but rare molecular aberrations in Chinese AML and MDS.
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PMID:IDH1 and IDH2 mutation analysis in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. 2199 50

Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P=0.0004; hazard ration 4.0, 95% confidence interval 1.9-8.8), revised International Prognostic Scoring System risk category (P<0.0001), and red cell transfusion need (P=0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P=0.001; hazard ration 7.0, 95% confidence interval 2.3-20.8). The presence of IDH2R140Q did not affect the overall (P=0.54) or leukemia-free (P=0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.
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PMID:Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. 2203 90

Myelodysplastic syndromes (MDS) are a heterogenous group of hematologic malignancies characterized by clonal expansion of BM myeloid cells with impaired differentiation. The identification of recurrent mutations in MDS samples has led to new insights into the pathophysiology of these disorders. Of particular interest is the recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1, and UTX) and DNA methylation (DNMT3A, IDH1/IDH2, and TET2) are recurrently mutated in MDS, providing an important link between genetic and epigenetic alterations in this disease. The mechanism by which these mutated genes contribute to disease pathogenesis is an active area of research, with a current focus on which downstream target genes may be affected. Recent advances from sequencing studies suggest that multiple mutations are required for MDS initiation and progression to acute myeloid leukemia (AML). The past several years have yielded many new insights, but the complete genetic landscape of MDS is not yet known. Moreover, few (if any) of the findings are sufficiently robust to be incorporated into routine clinical practice at this time. Additional studies will be required to understand the prognostic implications of these mutations for treatment response, progression to AML, and survival.
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PMID:Genetics of myelodysplastic syndromes: new insights. 2216 87

Until recently, the genetic aberrations that are causally linked to the pathogenesis of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms were largely unknown. Using novel technologies like high-resolution SNP-array analysis and next generation sequencing, various genes have now been identified that are recurrently mutated. Strikingly, several of the newly identified genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, and TET2) are involved in the epigenetic regulation of gene expression. Aberrant epigenetic modifications have been described in many types of cancer, including myeloid malignancies. It has been proposed that repression of genes that are crucial for the cessation of the cell cycle and induction of differentiation might contribute to the malignant transformation of normal hematopoietic cells. Several therapies that aim to re-express silenced genes are currently being tested in MDS, like histone deacetylase inhibitors and hypomethylating agents. It will be interesting to assess whether patients carrying mutations in epigenetic regulators respond differently to these novel forms of epigenetic therapies.
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PMID:Mutations in epigenetic regulators in myelodysplastic syndromes. 2223 28


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