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

Molecular cytogenetic techniques enabled us to clarify numerical and structural alterations previously detected by conventional cytogenetic techniques in 37 patients who had myelodysplastic syndromes with complex karyotypes. Using high-resolution comparative genomic hybridization (HR-CGH), we found the most recurrent alterations to be deletion of 5q (70%), 18q (35%), 7q (32%), 11q (30%), and 20q (24%), gain of 11q (35%) and 8q (24%), and trisomy of chromosome 8 (19%). Furthermore, in 35% of the patients, 20 amplifications were identified. These amplifications were shown by FISH to involve some genes previously described as amplified in hematological malignancies, such as ERBB2, MLL, and RUNX1. In addition, two other genes, BCL6 and BCL2, which are classically related to apoptosis and non-Hodgkin lymphoma, were shown for the first time to be involved in amplification. Genomic alterations involving different subtelomeric regions with losses in 4p16, 5p15.3, 6q27, 18p11.3, and 18q23 and gains in 1p36.3 and 19p13.3 were detected by HR-CGH. Array CGH analysis of the subtelomeric regions in some samples was able to confirm a number of these alterations and found some additional alterations not detected by conventional CGH.
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PMID:Analysis of myelodysplastic syndromes with complex karyotypes by high-resolution comparative genomic hybridization and subtelomeric CGH array. 1561 30

Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of acute myeloid leukemia 1 (AML1)/RUNX1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 in-frame to the novel partner gene FOG2/ZFPM2. The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses the transcriptional activity of both CBF and GATA1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and these proteins associate in a protein complex. These results suggest a central role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATAdevelopmental programs in the pathogenesis of myelodysplasia.
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PMID:AML1-FOG2 fusion protein in myelodysplasia. 1570 84

Chromosomal abnormalities are found by conventional cytogenetic (CC) analysis in about 50% of myelodysplastic syndromes (MDS) and 70% of acute myeloid leukemias (AML). When cytogenetic abnormalities are complex, multiplex fluorescence in situ hybridization (M-FISH) can help clarify complex chromosomal abnormalities and identify rearrangements with prognostic value or cryptic translocations, which could be preliminary steps in identifying new genes. We studied by M-FISH 28 cases of MDS and AML with complex chromosomal abnormalities, 10 of them were therapy-related. M-FISH allowed the characterization of unidentified chromosomal material in 26 cases (93%). One or several unbalanced rearrangements were observed in 27 cases (96%), generally interpreted as deletions or additional material by CC. Among those translocations, 4 involved 3 chromosomes. Eighteen cryptic translocations undetected by CC were found in 13 cases. By FISH analysis using locus specific probes, TP53 deletion, additional copies of MLL, and additional copies or deletions of RUNX1/AML1 were observed in 16, 4, and 3 cases, respectively. Thus, M-FISH is an important tool to characterize complex chromosomal abnormalities which identified unbalanced and cryptic translocations in 96% and 46% of the cases studied, respectively. Complementary FISH helped us identify involvement of TP53, MLL, and RUNX1/AML1 genes in 82% of cases, confirming their probable role in leukemogenesis.
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PMID:Role of multiplex FISH in identifying chromosome involvement in myelodysplastic syndromes and acute myeloid leukemias with complex karyotypes: a report on 28 cases. 1572 32

Complex karyotypes are seen in approximately 15% of de novo MDS/AML and in up to 50% of therapy-related MDS/AML. These patients represent a therapeutic challenge for which no current treatment approach is satisfactory. Therefore, a large number of genetic studies using cytogenetic molecular techniques have been performed to better define the chromosomal abnormalities in this poor-prognosis group. On the basis of the available data from several studies of AML with complex karyotypes, similar findings on recurrent breakpoints and frequently lost and gained chromosomal regions have been observed. The most frequent rearrangements, in all the published series, were unbalanced translocations leading to loss of chromosomal material. Overall, loss of 5q and/or 7q chromosomal material seemed the more common event, and losses of 5q, 7q, and 17p in combination were observed in many cases. Overrepresented chromosomal material from 8q, 11q23, 21q and 22q was found recurrently and in several cases this was due to the amplification of the MLL (located at 11q23) and AML1/RUNX1 (located at 22q22) genes. As a result of these findings, the presence of MLL copy gain/amplifications or losses of the short arm of chromosome 17, in association with 5/5q, have been found to be indicators of an extremely poor prognosis. Interestingly, this non-random pattern of DNA gains and losses, that characterizes AML cases with complex karyotypes, affects the gene expression pattern, and a specific expression profile, characterized by the upregulation of genes involved in the DNA repair and chromosome segregation pathways, has been recently reported. Therefore, a comprehensive genome-wide analysis of patients with AML or MDS with complex karyotypes has led to a better characterization of chromosomal aberrations. These specific alterations could be used in the near future as therapeutic targets or markers for the risk stratification of patients, detection of minimal residual disease and the development of new therapeutic interventions.
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PMID:Gains, losses and complex karyotypes in myeloid disorders: a light at the end of the tunnel. 1614 24

AML1 (RUNX1) encodes a DNA-binding subunit of the CBF transcription factor family and is required for the establishment of definitive hematopoiesis. AML1 is one of the most frequently mutated genes associated with human acute leukemia, suggesting that genetic alterations of the gene contribute to leukemogenesis. Here, we report the analysis of mice carrying conditional AML1 knockout alleles that were inactivated using the Cre/loxP system. AML1 was deleted in adult mice by inducing Cre activity to replicate AML1 deletions found in human MDS, familial platelet disorder and rare de novo human AML. At a latency of 2 months after induction, the thymus was reduced in size and frequently populated by immature double negative thymocytes, indicating defective T-lymphocyte maturation, resulting in lymphatic diseases with 50% penetrance, including atypical hyperplasia and thymic lymphoma. Metastatic lymphomas to the liver and the meninges were observed. Mice also developed splenomegaly with an expansion of the myeloid compartment. Increased Howell-Jolly body counts indicated splenic hypofunction. Thrombocytopenia occurred due to immaturity of mini-megakaryocytes in the bone marrow. Together with mild lymphocytopenia in the peripheral blood and increased fractions of immature cells in the bone marrow, AML1 deficient mice display features of a myelodysplastic syndrome, suggesting a preleukemic state.
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PMID:AML1 deletion in adult mice causes splenomegaly and lymphomas. 1624 65

Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q-, 5q-, 20q-, 6q-, 11q- and 13q-) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench and Fenaux). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD. Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells, the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (alpha-catenin) and c/EBPalpha, and implicating these genes as tumor suppressors. Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q- and (del)5q.
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PMID:Molecular Pathogenesis of MDS. 1630 74

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. Because MDS is a heterogeneous disorder, specific gene abnormalities implicated in the pathogenesis of MDS have been difficult to identify. Cytogenetic abnormalities are seen in half of the MDS patients and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Although point mutations of critical genes had been demonstrated to contribute to the development of MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene (which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of acute myeloid leukemia [AML]) in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lose trans-activation potential, which leads to a loss of AML1 function. These data indicate that AML1 point mutation is one of the major causes of MDS/AML, and "MDS/AML with AML1 mutation" represents a distinct clinicopathologic-genetic entity.
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PMID:Point mutations in the AML1/RUNX1 gene associated with myelodysplastic syndrome. 1639 Mar 15

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.
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PMID:Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. 1646 64

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. MDS is also a susceptibility to acute myeloid leukemia (AML) and shown to be extremely resistant to current therapeutic strategies. MDS in a subset of 10-20% of patients arise after previous chemotherapy or radiation exposure for other malignancies. Because MDS is a heterogeneous disorder, specific gene abnormalities playing a role in the myelodysplastic process have been difficult to identify. Cytogenetic abnormalities are seen in half of MDS patients, and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Genes more frequently implicated in the pathogenesis of MDS remain unknown. Although point mutations of critical genes have been demonstrated to contribute to the development MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene, which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of AML, in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt) and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most of AML1/RUNX1 mutants lose trans-activation potential, which leads to a loss of AML1 function indicating that AML1/RUNX1 dysfunction is one of the major pathogenesis of MDS/AML. Normalizing AML1 function or regulating cooperative gene mutations would provide an important clue for molecular target therapies.
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PMID:Implications of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome (MDS): future molecular therapeutic directions for MDS. 1701 76

Monoallelic RUNX1 mutations cause familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML). Sporadic mono- and biallelic mutations are found at high frequencies in AML M0, in radiation-associated and therapy-related myelodysplastic syndrome and AML, and in isolated cases of AML M2, M5a, M3 relapse, and chronic myelogenous leukemia in blast phase. Mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Most hematopoietic missense mutations in Runx1 involve DNA-contacting residues in the Runt domain, whereas the majority of CCD mutations in Runx2 are predicted to impair CBFbeta binding or the Runt domain structure. We introduced different classes of missense mutations into Runx1 and characterized their effects on DNA and CBFbeta binding by the Runt domain, and on Runx1 function in vivo. Mutations involving DNA-contacting residues severely inactivate Runx1 function, whereas mutations that affect CBFbeta binding but not DNA binding result in hypomorphic alleles. We conclude that hypomorphic RUNX2 alleles can cause CCD, whereas hematopoietic disease requires more severely inactivating RUNX1 mutations.
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PMID:Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. 1729 Feb 19


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