Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new myeloid leukemia cell line (CG-SH) with normal cytogenetics was established from a patient with acute myelogenous leukemia (AML) following myelodysplastic syndrome (MDS). The cells of CG-SH are immature blasts and have an immature myeloid phenotype (positive for myeloperoxidase, CD7, CD34, CD38, CD117, HLA-DR, negative for CD10, CD19, CD20, CD41, CD42). A partial expression of CD13, CD15, CD65 and a weak expression of CD33 and CD133 was noted. The cells are negative for EBER. By molecular analysis, a mutation of NRAS and heterozygous mutations of RUNX1 were detected. No mutations were detected in FLT3-ITD, MLL-PTD or NPM1. By real-time PCR, a series of 19 microRNAs was identified which are strongly expressed in CG-SH. In conclusion, a new cell line was established which will be useful for the study of AML with normal cytogenetics and mutations in NRAS and/or RUNX1.
 ...
PMID:Characterization of a new myeloid leukemia cell line with normal cytogenetics (CG-SH). 1941 91

Familial aggregation in patients with several haematological malignancies has been described, but the genetic basis for this familial clustering is not known. Few genes predisposing to familial haematological malignancies have been identified, among which RUNX1 and CEBPA have been described as predisposing genes to acute myeloid leukemia (AML). Recent studies on RUNX1 suggest that germline mutations in this gene predispose to a larger panel of familial haematological malignancies than AML. In order to strengthen this hypothesis, we have screened CEBPA for germline mutations in several families presenting aggregation of hematological malignancies (including chronic or acute, lymphoid or myeloid leukemias, Hodgkin's or non Hodgkin's lymphomas, and myeloproliferative or myelodysplastic syndromes) with or without solid tumours. Although no deleterious mutations were found, we report two novel and rare variants of uncertain significance. In addition, we confirm that the in frame insertion c.1175_1180dup (p.P194_H195dup) is a germline polymorphism.
 ...
PMID:Molecular study of CEBPA in familial hematological malignancies. 1973 Oct 81

The primary pathology in many cases of myelodysplasia (MDS) and acute myeloid leukemia (AML) remains unknown. In some cases, two or more affected members have been identified in the same family. To date, mutations in two genes have been directly implicated: the hematopoietic transcription factors RUNX1 (runt-related transcription factor 1) and CEBPA (CCATT-box enhancer binding protein alpha). However, there are also other familial cases of MDS/AML where the genetic basis remains unknown. Both MDS, and to a lesser extent AML, have been observed in cases of the bone marrow failure syndrome dyskeratosis congenita, in which telomerase mutations have been identified. Recently, an increased incidence of telomerase reverse transcriptase mutations has been reported in a series of de novo AML. We have now identified novel mutations in the telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT) within 4 of 20 families presenting with familial MDS/AML. Functional analysis has demonstrated that all mutations adversely impact on telomerase activity in vitro, and affected individuals have short telomeres. These families, in conjunction with a review of previously published cases, help to further define the pathological role of telomerase mutations in MDS/AML and have implications for the biology, treatment and screening regimen of de novo cases.
 ...
PMID:Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. 1976 Jul 49

Somatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.
 ...
PMID:AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. 1980 97

Little was known about the mechanisms for myeloproliferative diseases (MPD) until 2005 when an activating mutation in the JAK2 tyrosine kinase (JAK2 V617F) was identified in >95% of patients with polycythemia vera (PV), and in a significant proportion of patients with essential thormbocythemia (ET) and primary myelofibrosis (PMF). Furthermore, activating abnormalities of some tyrosine kinases were identified in MPD and related diseases, suggesting that constitutive activation of the signaling pathway is a unifying feature of these diseases. On the other hand, the molecular mechanism of myelodysplastic syndromes (MDS) is still poorly understood. Recent study revealed that two types of AML1/RUNX1 mutants function via distinct molecular mechanisms to produce mutant-specific phenotypes of MDS. The mechanisms of MPD and MDS gradually become clear.
 ...
PMID:[Molecular mechanisms in myeloproliferative diseases and myelodysplastic syndromes]. 1986 Jan 87

A proportion of cytogenetic abnormalities in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) may escape detection by high-resolution genomic technologies, but can be identified by conventional cytogenetic and molecular analysis. Here, we report the detection of a reciprocal translocation t(7;21)(p22;q22) in the marrow of two adults with MDS and AML, using conventional cytogenetic analysis and fluorescence-in situ-hybridization (FISH). Reverse-transcription polymerase chain reaction (RT-PCR) and sequence analysis identified a fusion between RUNX1 and the gene encoding ubiquitin specific peptidase-42 (USP42), with splice-variants and variable break-points within RUNX1. Combined cytomorphology and FISH studies in MDS marrow revealed abnormal RUNX1 signals within megakaryocytes, suggesting that the acquisition of t(7;21)(p22;q22) does not confer complete differentiation arrest and may represent an early genetic event in leukaemogenesis. Single nucleotide polymorphism-arrays failed to detect additional sub-microscopic genomic changes predisposing to or associated with t(7;21). Molecular analysis of 100 MDS and AML marrow specimens by RT-PCR did not reveal new cases with the RUNX1-USP42 fusion. Thus, our studies have identified t(7;21)(p22;q22) as a rare but recurrent abnormality in MDS/AML, with the existence of alternative spliced forms of the RUNX1-USP42 transcript in different patients. Further studies are required to identify the potential contribution of these splice-variants to disease heterogeneity.
 ...
PMID:Molecular characterisation of a recurrent, semi-cryptic RUNX1 translocation t(7;21) in myelodysplastic syndrome and acute myeloid leukaemia. 2006 52

The GFI1 gene encodes a transcriptional repressor, which regulates myeloid differentiation. In the mouse, Gfi1 deficiency causes neutropenia and an accumulation of granulomonocytic precursor cells that is reminiscent of a myelodysplastic syndrome. We report here that a variant allele of GFI1 (GFI1(36N)) is associated with acute myeloid leukemia (AML) in white subjects with an odds ratio of 1.6 (P < 8 x 10(-5)). The GFI1(36N) variant occurred in 1806 AML patients with an allele frequency of 0.055 compared with 0.035 in 1691 healthy control patients in 2 independent cohorts. We observed that both GFI1 variants maintain the same activity as transcriptional repressors but differ in their regulation by the AML1/ETO (RUNX1/RUNX1T1) fusion protein produced in AML patients with a t(8;21) translocation. AML1/ETO interacts and colocalizes with the more common GFI1(36S) form in the nucleus and inhibits its repressor activity. However, the variant GFI1(36N) protein has a different subnuclear localization than GFI1(36S). As a consequence, AML1/ETO does not colocalize with GFI1(36N) and is unable to inhibit its repressor activity. We conclude that both variants of GFI1 differ in their ability to be regulated by interacting proteins and that the GFI1(36N) variant form exhibits distinct biochemical features that may confer a predisposition to AML.
 ...
PMID:A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia. 2007 57

Newborns and children with Down syndrome (DS) often present with congenital transient leukemia and have an increased risk of acute myeloid leukemia and acute lymphoblastic leukemia. Thus, constitutional trisomy 21 represents an excellent model to study the origin and progression of leukemia. However, trisomy 21 can also occur as a somatic chromosome aberration leading to sporadic leukemia. During the 50 years, since the discovery of constitutional trisomy 21 in DS, we have also learned that this small chromosome 21, harboring about 300 genes, may be involved in numerous structural aberrations, e.g., translocations, deletions, and amplifications, in leukemias, lymphomas, and solid tumors. Moreover, genes located on chromosome 21 have been identified that play an important role in tumorigenesis. Somatic mutations of several of these genes have been shown to be associated with different solid tumors, but also constitutional mutations of a specific gene on chromosome 21 leading to myelodysplastic syndromes and acute myeloid leukemia have been described. In this review, the specific forms of myeloid leukemia as well as of acute lymphoblastic leukemia in children with DS will be presented and possible explanations for the paucity of solid tumors in DS will be given. Somatic numerical as well as structural chromosome 21 aberrations in association with leukemias will be described. Finally, the nature and function of specific genes, like RUNX1, TMPRSS2, and TFF, located in 21q, and their role in tumorigenesis will be exemplified.
 ...
PMID:The role of chromosome 21 in hematology and oncology. 2023 85

The myelodysplastic syndromes (MDS) are frequently associated with clonally restricted cytogenetic abnormalities, but until recently, the molecular pathobiology underlying this diverse group of neoplastic bone marrow disorders has been largely obscure. During the last 10 years, many investigative groups have applied the formidable power of new molecular biology techniques to hunt for recurrent genetic alterations in MDS primary cells. Several genetic abnormalities, including mutations in RUNX1 (AML1), TET2, ASXL1 and TP53, have been discovered in a substantial fraction of MDS cases; genes rearranged or mutated less commonly in MDS include IER3, ATRX, RAS and FLT3. Furthermore, haploinsufficiency and expression changes in RPS14, miR-145 and miR-146a, CDC25c, PP2A and SPARC in the absence of point mutations have also been implicated in MDS pathobiology. A major challenge will be to determine which of these mutations are causative "drivers" either in the development or progression of MDS, which might be therapeutically important because they predict response to treatment, and which are merely "passengers" along for the ride that alter phenotype but have no effect on the natural history of the disease. While the altered cellular biology of MDS is also increasingly well-understood, many mysteries remain. Abnormalities in iron regulation, microenvironment interactions, regulation of apoptosis and oxidative damage/DNA repair may all play an important pathobiological role. By gaining a deeper understanding of the mechanisms of these complex and heterogeneous diseases, we will hopefully improve our ability to treat our patients with MDS beyond the therapies with limited effectiveness that are available at present.
 ...
PMID:The molecular pathogenesis of myelodysplastic syndromes. 2059 88

Hematopoietic stem cells (HSCs) are functionally defined as cells that upon transplantation into irradiated or otherwise immunocompromised adult organisms provide long-term reconstitution of the entire hematopoietic system. They emerge in the vertebrate conceptus around midgestation. Genetic studies have identified a number of transcription factors and signaling molecules that act at the onset of hematopoiesis, and have begun to delineate the molecular mechanisms underlying the formation of HSCs. One molecule that has been a particularly useful marker of this developmental event in multiple species is Runx1 (also known as AML1, Pebp2alpha). Runx1 is a sequence-specific DNA-binding protein, that along with its homologues Runx2 and Runx3 and their shared non-DNA binding subunit CBFbeta, constitute a small family of transcription factors called core-binding factors (CBFs). Runx1 is famous for its role in HSC emergence, and notorious for its involvement in leukemia, as chromosomal rearrangements and inactivating mutations in the human RUNX1 gene are some of the most common events in de novo and therapy-related acute myelogenous leukemia, myelodysplastic syndrome and acute lymphocytic leukemia. Here we will review the role of Runx1 in HSC emergence in the mouse conceptus and describe some of the genetic pathways that operate upstream and downstream of this gene. Where relevant, we will include data obtained from other species and embryonic stem (ES) cell differentiation cultures.
 ...
PMID:Hematopoietic stem cell emergence in the conceptus and the role of Runx1. 2071 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>