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)

The AML1/EVI-1 chimeric gene is generated by the t(3;21)(q26;q22) translocation and plays a pivotal role in progression of hematopoietic stem cell malignancies such as chronic myelocytic leukemia and myelodysplastic syndrome. In AML1/EVI-1, an N-terminal half of AML1 including a runt homology domain is fused to the entire zinc-finger EVI-1 protein. AML1 is essential for hematopoietic cell development in fetal liver and its lineage-specific differentiation in adult. In contrast, EVI-1 is barely expressed in normal hematopoietic cells, but it is overexpressed in chronic myelocytic leukemia in blastic crisis and myelodysplastic syndrome-derived leukemia. There are at least four mechanisms identified in AML1/EVI-1 fusion protein that possibly lead into malignant transformation of hematopoietic stem cells. Firstly, AML1/EVI-1 exerts dominant-negative effects over AML1-induced transcriptional activation. Although target genes repressed by AML1/EVI-1 are still not known, binding competition to a specific DNA sequence and histone deacetylase recruitment through a co-repressor CtBP in EVI-1 part are conceivable underlying mechanisms for the dominant-negative effects. Secondly, AML1/EVI-1 interferes with TGF beta signaling and antagonizes the growth-inhibitory effects of TGF beta. The first zinc-finger domain of EVI-1 associates with Smad3, a TGF beta signal transducer, and represses its transcriptional activity by recruiting histone deacetylase through CtBP that interacts with EVI-1. Thirdly, AML1/EVI-1 blocks JNK activity and prevents stress-induced apoptosis. AML1/EVI-1 associates with JNK through the first zinc-finger domain of EVI-1 and disturbs the association between JNK and its substrates. Lastly, AML1/EVI-1 enhances AP-1 activity by activating the c-Fos promoter depending on the second zinc-finger domain of EVI-1, and promotes cell proliferation. All these functions cooperatively contribute to the malignant transformation of the hematopoietic stem cells by AML1/EVI-1.
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PMID:Molecular mechanisms of leukemogenesis by AML1/EVI-1. 1515 82

We describe a patient with a suspected myelodysplastic syndrome that developed in association with a neurologic disorder resembling subacute combined degeneration but without vitamin B12 deficiency. Ultimately, the hematologic manifestations and the neurologic syndrome were linked to severe copper deficiency. Prompt and complete reversal of the hematologic abnormalities occurred with copper replacement. Serum copper determination should be included in the work-up of patients with anemia and leukopenia of unclear etiology who have associated myeloneuropathy. The hematologic picture can resemble sideroblastic anemia or myelodysplastic syndrome. Hyperzincemia can be an accompanying abnormality even without exogenous zinc ingestion. The reason for the copper deficiency may not be evident.
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PMID:"Myelodysplasia," myeloneuropathy, and copper deficiency. 1643 90

Raised percentage hypochromic red cells (%HRC) were detected at diagnosis in 10 of 34 consecutive patients with low-risk myelodysplastic syndrome (MDS) [refractory anemia (RA) (4/26) and RA with ring sideroblasts (6/8)], all of whom had normal or increased serum ferritin and bone marrow iron stores. Elevated %HRC has persisted in all 10 cases and subsequently developed in another RA patient who later had a complete remission of MDS with normalisation of %HRC after a respiratory tract infection. A strong positive correlation was found between %HRC and erythrocyte zinc protoporphyrin levels in 11 MDS patients tested (p=0.01), suggesting that functional iron deficiency contributes to ineffective erythropoiesis in cases of MDS with raised %HRC. Five of seven patients with elevated %HRC had satisfactory haemoglobin responses to a trial of human recombinant erythropoietin without iron supplementation.
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PMID:Myelodysplastic patients with raised percentage of hypochromic red cells have evidence of functional iron deficiency. 1656 20

EVI1 is an aggressive nuclear oncoprotein deregulated by recurring chromosomal abnormalities in myelodysplastic syndrome (MDS). The expression of the corresponding gene is a very poor prognostic marker for MDS patients and is associated with severe defects of the erythroid lineage. We have recently shown that the constitutive expression of EVI1 in murine bone marrow results in a fatal disease with features characteristic of MDS, including anemia, dyserythropoiesis, and dysmegakaryopoiesis. These lineages are regulated by the DNA-binding transcription factor GATA1. EVI1 has two zinc finger domains containing seven motifs at the N terminus and three motifs at the C terminus. Supported by results of assays utilizing synthetic DNA promoters, it was earlier proposed that erythroid-lineage repression by EVI1 is based on the ability of this protein to compete with GATA1 for DNA-binding sites, resulting in repression of gene activation by GATA1. Here, however, we show that EVI1 is unable to bind to classic GATA1 sites. To understand the mechanism utilized by EVI1 to repress erythropoiesis, we used a combination of biochemical assays, mutation analyses, and in vitro bone marrow differentiation. The results indicate that EVI1 interacts directly with the GATA1 protein rather than the DNA sequence. We further show that this protein-protein interaction blocks efficient recognition or binding to DNA by GATA1. Point mutations that disrupt the geometry of two zinc fingers of EVI1 abolish the protein-protein interaction, leading to normal erythroid differentiation of normal murine bone marrow in vitro.
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PMID:Point mutations in two EVI1 Zn fingers abolish EVI1-GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. 1695 86

The ecotropic viral integration site 1 (EVI1) gene was identified as a common locus of retroviral integration in myeloid tumors found in mice. EVI1 gene is highly conserved through evolution and human gene EVI1 on chromosome 3q26 encodes zinc fingers-containing transcription factor. EVI1 is expressed in nonhematopoietic tissues but not in normal blood or bone marrow. EVI1 was detected in hematopoietic cells in retrovirus-induced myeloid leukemias in mice and several reports documented EVI1 expression in human myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. EVI1 is abnormally expressed in human myeloid leukemias that are associated with the t(3;3)(q21;q26), t(3;21)(q26;q22), inv(3)(q21q26) and other chromosomal rearrangements. EVI1 is overexpressed in some ovarian cancers and human colon cancer cell lines and may play a role in the initiation and/or progression of solid tumors, as well as hematopoietic malignancies. EVI1 is a transcriptional repressor which inhibits transforming growth factor beta (TGFbeta) family signalling by binding signal transducers (Smad proteins) and recruiting transcriptional corepressors. TGFbeta is an important regulator of proliferation, differentiation, apoptosis and migration of cells. EVI1 inhibits TGFbeta-mediated apoptosis. Knockdown of EVI1 function by small interference RNA increases the sensitivity of malignant cells to TGFbeta-mediated or other inducer-mediated apoptosis. Overexpressed EVI-1 blocks granulocyte and erythroid differentiation and possess the ability of growth promotion in some types of cells. EVI1 functions in some cases as a transcriptional activator which stimulates for example GATA2 and GATA3 promoters. The study of EVI1 target genes will help to clear the mechanism by which EVI1 upregulates cell proliferation, impairs cell differentiation, and induces cell transformation.
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PMID:[EVI1 and its role in myelodysplastic syndrome, myeloid leukemia and other malignant diseases]. 1699 17

The Wilms tumor gene WT1 encodes a zinc-finger transcription factor that is inactivated in a subset of pediatric kidney cancers. During embryogenesis, WT1 is expressed in a time- and tissue-specific manner in various organs including gonads and kidney but also in the hematopoietic system. Although widely regarded as a tumor suppressor gene, wild-type WT1 is overexpressed in a variety of hematologic malignancies, most notably in acute lymphoblastic leukemia as well as myelodysplastic syndromes. Reduction of WT1 expression levels leads to decrease of proliferation and apoptosis of leukemic cells, suggesting that in certain contexts WT1 might act as an oncogene. We show here that histone deacetylase inhibitors like Trichostatin A (TSA) can promptly and dramatically downregulate Wt1 expression levels in different cell lines. This effect was mostly due to the cessation of transcription and was mediated by sequences located in intron 3 of Wt1. In addition, TSA also caused enhanced degradation of the Wt1 protein by the proteasome. This was at least in part due to induction of the ubiquitin-conjugating enzyme UBCH8. Thus, downregulation of Wt1 expression might contribute to the beneficial effects of histone deacetylase inhibitors that are currently used in clinical trials as cancer therapeutics.
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PMID:TSA downregulates Wilms tumor gene 1 (Wt1) expression at multiple levels. 1853 6

Copper is an essential cofactor in many enzymatic reactions vital to the normal function of the hematologic, vascular, skeletal, antioxidant, and neurologic systems. Copper deficiency in the United States is believed to be relatively rare but has been described in the setting of zinc supplementation, myelodysplastic syndrome, use of parenteral nutrition and chronic tube feeding, and in various malabsorptive syndromes, including following gastrectomy and gastric bypass surgery. Features of copper deficiency include hematologic abnormalities (anemia, neutropenia, and leukopenia) and myeloneuropathy; the latter is a rarer and often unrecognized complication of copper deficiency. We here describe two patients who presented with severe gait abnormalities and anemia combined with neutropenia several years after roux-en-Y gastric bypass (RYGB) surgery for obesity who were found to be severely copper deficient. Intravenous copper repletion resulted in the rapid correction of hematologic indices; combined intravenous and oral copper supplementation and eventual oral copper supplements alone normalized serum copper levels in each patient, but resulted in only partial resolution of the neurologic deficits. This report serves to alert physicians of the association between RYGB procedures and subsequent copper deficiency in order to avoid diagnostic delays and to improve treatment outcomes.
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PMID:Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. 1985 58

Retinoids triggers differentiation of acute promyelocytic leukemia (APL) blasts by transcriptional regulation of myeloid regulatory genes. Using a microarray approach, we have identified a novel retinoid-responsive gene (CXXC5) encoding a nuclear factor, retinoid-inducible nuclear factor (RINF), that contains a CXXC-type zinc-finger motif. RINF expression correlates with retinoid-induced differentiation of leukemic cells and with cytokine-induced myelopoiesis of normal CD34(+) progenitors. Furthermore, short hairpin RNA (shRNA) interference suggests for this gene a regulatory function in both normal and tumoral myelopoiesis. Interestingly, RINF localizes to 5q31.3, a small region often deleted in myeloid leukemia (acute myeloid leukemia [AML]/myelodysplasia [MDS]) and suspected to harbor one or several tumor suppressor gene.
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PMID:Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesis. 1918 10

Acquired copper deficiency has been recognised as a rare cause of anaemia and neutropenia for over half a century. Copper deficiency myelopathy (CDM) was only described within the last decade, and represents a treatable cause of non-compressive myelopathy which closely mimics subacute combined degeneration due to vitamin B12 deficiency. Here, 55 case reports from the literature are reviewed regarding their demographics, aetiology, haematological and biochemical parameters, spinal imaging, treatment and outcome. The pathophysiology of disorders of copper metabolism is discussed. CDM most frequently presented in the fifth and sixth decades and was more common in women (F:M = 3.6:1). Risk factors included previous upper gastrointestinal surgery, zinc overload and malabsorption syndromes, all of which impair copper absorption in the upper gastrointestinal tract. No aetiology was established in 20% of cases. High zinc levels were detected in some cases not considered to have primary zinc overload, and in this situation the contribution of zinc to the copper deficiency state remained unclear. Cytopenias were found in 78%, particularly anaemia, and a myelodysplastic syndrome may have been falsely diagnosed in the past. Spinal MRI was abnormal in 47% and usually showed high T2 signal in the posterior cervical and thoracic cord. In a clinically compatible case, CDM may be suggested by the presence of one or more risk factors and/or cytopenias. Low serum copper and caeruloplasmin levels confirmed the diagnosis and, in contrast to Wilson's disease, urinary copper levels were typically low. Treatment comprised copper supplementation and modification of any risk factors, and led to haematological normalisation and neurological improvement or stabilisation. Since any neurological recovery was partial and case numbers of CDM will continue to rise with the growing use of bariatric gastrointestinal surgery, clinical vigilance will remain the key to minimising neurological sequelae. Recommendations for treatment and prevention are made.
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PMID:Copper deficiency myelopathy. 2023 10

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
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PMID:Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. 2215 38


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