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Query: UNIPROT:P06889 (Mol)
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The evolution of bone marrow failure syndromes such as aplastic anemia (AA) to clonal hematologic diseases such as myelodysplastic syndrome is well recognized. Cytogenetic abnormalities are commonly seen late events, particularly aneuploidy of chromosomes 7 and 8. A proportion of bone marrow failure patients may also develop aneuploidy that is detectable by fluorescence in situ hybridization but not by standard cytogenetic analysis. The molecular basis for aneuploidy in this setting is currently unknown but may include abnormalities in the mitotic spindle checkpoint. For this reason, we searched for mutations in the mitotic spindle checkpoint genes hBUB1 and hMAD2, and also examined the expression of hBUB1 in cells of bone marrow failure patients. No pathogenic mutations were found in 59 patients. Of 170 bone marrow failure patients, less than one-third expressed hBUB1 transcript. Gene expression profiling confirmed a significant down-regulation of hBUB1 message in patients. We conclude that mutations in mitotic spindle checkpoint genes do not account for aneuploidy in marrow failure states. However, we cannot exclude epigenetic inactivation of hBUB1 as a potential mechanism in some patients.
Blood Cells Mol Dis
PMID:Genetic and transcriptional analysis of spindle checkpoint genes in bone marrow failure patients. 1273 50

Changes in key enzymes of oxidative metabolism at the mitochondrial level are known to be associated with the aging process, apoptosis, and many diseases. Considering the risk of acquiring a myelodysplastic syndrome (MDS) with age, the aim of this study was to quantify mRNA synthesis of the carnitine palmitoyltransferases (CPT1 and CPT2), carnitine acetyltransferase (CRAT), human specific microsomal CPT, and OCTN2 (organic cation transporter) in mononuclear cells of healthy humans of different age groups and MDS patients. Using quantitative reverse transcriptase real-time PCR we compared mRNA synthesis of the above mentioned enzymes in mononuclear cells from peripheral blood of 23 healthy persons (mean age 45 years), 9 blood and 22 bone marrow samples of 31 MDS patients with varying proportions of apoptotic cells (mean age 78 years), and blood samples of 30 age-matched controls. In addition, plasma carnitine levels were determined. Compared to younger adults, there was a 50% downregulation of CPT1 in elderly persons and in MDS patients. Reduction in CRAT, CPT 2, and OCTN2 was more than 85%. Reduction in microsomal CPT was more pronounced in MDS patients than in age-matched controls (96% vs. 43%). In MDS bone marrow cells there was a negative correlation of CPT1 and CRAT with the relative proportion of apoptotic cells. Plasma carnitine values were similar in all groups. The described reduction in transcription of different genes in blood cells which is well known in different tissues may reflect a systemic signaling process, associated with aging, apoptosis, and MDS.
J Mol Med (Berl) 2003 Jul
PMID:Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes. 1280 1

Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl-2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl-2 was performed using annexin V-biotin conjugate antibody and anti-human Bcl-2 antibody respectively, followed by streptavidine-peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl-2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl-2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl-2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.
J Cell Mol Med
PMID:Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro-apoptotic cytokines. 1459 56

Mutations in the gene for epsilon sarcoglycan (epsilon-SG) are associated with a disorder of the central nervous system, the myoclonus-dystonia syndrome (MDS; DYT11). In contrast, mutations of other sarcoglycan family members lead to limb-girdle muscular dystrophies. To establish the framework for functional studies of epsilon-SG, we cloned rat epsilon-SG cDNA, quantified epsilon-SG mRNA levels in neural and non-neural tissues at different developmental time points with relative quantitative multiplex real-time reverse transcriptase PCR (RT-PCR), and characterized the distribution of epsilon-SG mRNA in brain with in situ hybridization. Rat epsilon-SG cDNA contains an open reading frame (ORF) of 1311 bp that encodes a 437-amino acid (aa) protein with 95.9% and 98.2% identity to human and mouse epsilon-SG amino acid sequences, respectively. Using real-time RT-PCR, epsilon-SG was detected in both neural (cerebellar cortex, striatum, cerebral cortex, thalamus, hippocampus) and non-neural (muscle, liver, kidney, heart) tissues at each developmental time point tested [Embryonic Day 20 (E20), Postnatal Day 1 (P1), P7, P14, P36, 6 months, 1.5 years). Levels of epsilon-SG mRNA were highest at E20 in all tissues. The developmental regulation of epsilon-SG mRNA expression was most striking in muscle with E20 and early postnatal epsilon-SG mRNA levels over 10 times higher than those seen in adult rats. In adult rats, epsilon-SG mRNA levels were several-fold higher in brain, particularly cerebellar cortex, than in muscle. Radioactive in situ hybridization showed that epsilon-SG mRNA was widely distributed in rat brain. Robust hybridization signal was obtained from regions with dense neuronal packing such as the hippocampus, cerebellar molecular layer, and cerebral cortex. Our results suggest that epsilon-SG participates in the development of both neural and non-neural tissues and contributes to neuronal structure in the adult central nervous system.
Brain Res Mol Brain Res 2003 Nov 26
PMID:Cloning, developmental regulation and neural localization of rat epsilon-sarcoglycan. 1462 80

Primary familial and congenital polycythemia (PFCP), inherited as an autosomal dominant trait, has been reported to be associated with mutations in the gene encoding the erythropoietin receptor (EpoR). The clinical features include the presence of isolated erythrocytosis, low erythropoietin (Epo) levels, normal hemoglobin-oxygen dissociation curve, hypersensitivity of erythroid progenitors to exogenous Epo in vitro and no progression to leukemia or myelodysplastic syndrome. Less than 15% of PFCP families have an identifiable EPOR mutation. Abnormalities of other genes are therefore likely responsible for the phenotype of the majority PFCP patients. In this study we report a family segregating PFCP with an autosomal dominant pattern of inheritance, where 7 of 14 members of the family were affected in four generations. This family was studied previously and an EPOR mutation was ruled out by sequencing and by genetic means. Here, we confirmed by linkage analysis that the disease phenotype was not linked to the Epo and EPOR genes. We then performed a genomewide screen with 410 polymorphic markers at average spacing 7.67 cM to locate the chromosomal region responsible for PFCP. We identified a region in 7q22.1-7q22.2 with a suggestive LOD score of 1.84, from our data this is the most likely location of a candidate region responsible for PFCP in this family.
Blood Cells Mol Dis
PMID:Possible primary familial and congenital polycythemia locus at 7q22.1-7q22.2. 1463 47

Hydroquinone is a myelotoxin that is found in many foods and is also formed through the metabolism of benzene. Human exposure to benzene is associated with the development of myelodysplastic syndrome and acute myelogenous leukemia. Hydroquinone is genotoxic in several in vitro and in vivo test systems, inducing micronuclei (MN), sister-chromatid exchange (SCE), and chromosomal aberrations. Glutathione S-transferases (GSTs) are a superfamily of polymorphic enzymes involved in the conjugation of reactive chemical intermediates to soluble forms. These enzymes play a key role in the detoxification of endogenous and exogenous compounds, and the polymorphic genes GSTM1, GSTT1, and GSTP1 have been associated with the differential metabolism of several genotoxicants. In the present study, we have evaluated the effect of GSTM1, GSTT1, and GSTP1 polymorphisms on the frequency of MN and SCE induced by hydroquinone in human lymphocytes. Lymphocytes were obtained from 15 healthy non-smoking donors, and their GSTM1, GSTT1, and GSTP1 genotypes determined. Treatment of cultures of the lymphocytes with hydroquinone significantly increased the overall frequencies of MN and SCE (P<0.0001). Individuals with the GSTM1 null genotype had a significantly higher frequency of MN compared with GSTM1-present individuals (P=0.013); in contrast, the GSTM1 genotype had no effect on hydroquinone-induced SCE frequency. The other polymorphisms did not significantly affect the frequencies of MN or SCE. These results suggest that GSTM1 is involved in the metabolic fate of hydroquinone and that polymorphisms in GSTM1 could be related to inter-individual differences in DNA damage arising from the exposure to this compound.
Environ Mol Mutagen 2004
PMID:GSTM1, GSTT1, and GSTP1 genotypes and the genotoxicity of hydroquinone in human lymphocytes. 1514 65

Double minutes (dmin), the cytogenetic hallmark of genomic amplification, are found in approximately 1% of karyotypically abnormal acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS). The MYC gene at 8q24 has been reported to be amplified in the majority of the cases, and generally it has been assumed that MYC is the target gene. However, only a few studies have focused on the extent of the amplicon or on the expression patterns of the amplified genes. We have studied six cases (five AML and one MDS) with MYC-containing dmin. Detailed fluorescence in situ hybridization analyses identified a common 4.3 Mb amplicon, with clustered proximal and distal breakpoints, harboring eight known genes (C8FW, NSE2, POU5FLC20, MYC, PVT1, AK093424, MGC27434 and MLZE). The corresponding region was deleted in one of the chromosome 8 homologues in five of the six cases, suggesting that the dmin originated through extra replication (or loop-formation)--excision--amplification. Northern blot analysis revealed that MYC was not overexpressed. Instead, the C8FW gene, encoding a phosphoprotein regulated by mitogenic pathways, displayed increased expression. These results exclude MYC as the target gene and indicate that overexpression of C8FW may be the functionally important consequence of 8q24 amplicons in AML and MDS.
Hum Mol Genet 2004 Jul 15
PMID:Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies. 1516 36

We reanalysed published data to evaluate whether climate and habitat are barriers to dispersal in one of the most mobile and widely distributed mammals, the grey wolf (Canis lupus). Distance-based redundancy analysis (dbRDA) was used to examine the amount of variation in genetic distances that could be explained by an array of environmental factors, including geographical distance. Patterns in genetic variation were also examined using MDS plots among populations and relationships between genetic structure and individual environmental variables were further explored using the BIOENV procedure. We found that, contrary to a previous report, a pattern of isolation with distance is evident on a continental scale in the North American wolf population. This pattern is apparently related to climate and habitat. Specifically, vegetation types appear to play a role in the genetic dissimilarities among populations. When we controlled for the effect of spatial variation, climate was still associated with genetic distance. Further, partitioning of geographical distances into latitudinal and longitudinal axes revealed that the east-west gradient had the strongest relationship with genetic distance. We suggest two possible mechanisms by which environmental conditions may influence the dispersal decisions made by wolves.
Mol Ecol 2004 Aug
PMID:Climate and habitat barriers to dispersal in the highly mobile grey wolf. 1524 20

We present an update of our results with transplantation of highly purified stem cells from one to three loci mismatched parental donors. Sixty-three pediatric patients with acute lymphoblastic leukemias (n = 32), acute myeloid, chronic myeloid and myelomonocytic leukemias (n = 13), myelodysplastic syndromes (n = 4), lymphomas (n = 4), and various nonmalignant diseases (n = 10) underwent transplantation. Mobilized peripheral-blood stem cells were selected with either anti-CD34- or anti-CD133-coated microbeads. Patients received a median of 19.5 x 10(6) purified cells and <25,000 CD3+ T lymphocytes per kilogram, with no regular posttransplant pharmacological immunosuppression. Engraftment occurred in 98% of patients (primary sustained engraftment, 83%; engraftment after reconditioning/stem cell boosts, 15%). Moreover, all survivors but one had a stable three-lineage engraftment with a median follow up of 4.1 years (range 0.6-8 years). Primary acute graft-versus-host disease (GvHD) grade II was seen in only 7% of patients. No severe primary acute GvHD grades III-IV occurred. Thirteen percent of the patients developed transient chronic GvHD. Probability of disease-free survival (DFS) at 3 years was 60% for patients with nonmalignant diseases and 48% for patients with acute lymphatic leukemia (ALL)/non-Hodgkin lymphoma (NHL) in complete remission (CR)1-3. None of the ALL/NHL patients with active disease survived. Children with acute and chronic myeloid leukemias had a poorer outcome (3-year DFS = 18%), whereas two of four patients with myelodysplastic syndrome (MDS) are alive. Relapse probability of the whole group was not significantly increased when compared to a historical control group. The incidence of lethal viral infections was 18% between 1995 and 2002 and has since been reduced to 8% by the introduction of new therapeutic strategies. In summary, the use of stem cells from haploidentical parental donors should be strongly considered in all children who need transplantation but lack an identical donor.
Blood Cells Mol Dis
PMID:Long-term outcome after haploidentical stem cell transplantation in children. 1552 45

GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.
Mol Cell Biol 2004 Dec
PMID:Leukemogenesis caused by incapacitated GATA-1 function. 1557 84


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