Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A somatic mutation(s), acquired during the evolution of preleukemia in a 75-year-old Caucasian male of North European origin, resulted in a marked decrease in alpha-globin mRNA. The small amount of alpha-globin mRNA present in bone marrow cells was normally processed, had a normal (alpha 1/alpha 2)-globin mRNA ratio, and was translated normally. No detectable zeta-globin mRNA was found. The alpha- and zeta-globin genes were both hypomethylated and restriction endonuclease maps of the alpha- and zeta-globin genes were comparable in the patient's marrow and fibroblast DNA. The data are most consistent with the acquisition of a mutation(s) that resulted in decreased expression of all four alpha-globin genes.
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PMID:Acquired alpha-thalassemia in preleukemia is due to decreased expression of all four alpha-globin genes. 613 71

The presence of hemoglobin H (beta 4), resulting from a deficiency of alpha-globin chain synthesis, was observed as an acquired characteristic in the red cells of five elderly patients with myeloproliferative disorders or preleukemia. The variability in amount of hemoglobin H and in the alpha/beta globin synthesis ratios in these patients is most likely explained by the relative proportions of normal and abnormal cell populations in the peripheral blood, since some reticulocyte fractions with balanced alpha/beta globin synthesis ratios and others with almost no detectable alpha-chain production could be obtained from these patients. In one patient, the hemoglobin H virtually disappeared despite continuing disease. The amount of cytoplasmic alpha-mRNA matched the proportion of alpha-chain synthesis and, in one patient, this was also true for nuclear RNA. However, extensive analysis of the alpha-globin gene complex by restriction endonuclease mapping revealed no detectable rearrangements of the normal gene organization in any of these patients, suggesting that transcription of each pair of alpha-globin genes on each chromosome 16 is defective. These observations have important implications for both the normal regulation of alpha-globin gene expression and the molecular basis of the underlying defect that is associated with the neoplastic transformation of these cells.
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PMID:Clinical features and molecular analysis of acquired hemoglobin H disease. 688 Nov 69

We performed a longitudinal analysis of the karyotypes and N-ras gene configuration of bone marrow cells in 35 patients with myelodysplastic syndrome (MDS). Karyotypic evolution was found in eight patients, and was associated with disease progression, including leukemic transformation, in all the patients. We identified N-ras mutations in six patients, using a polymerase chain reaction (PCR) technique, in which oligonucleotide primers were constructed with induced mismatches, followed by endonuclease digestion. Direct sequencing confirmed single base substitutions at codon 12 in two patients and at codon 13 in four. The incidence of N-ras gene mutations was significantly higher in the karyotypically evolved group (five of eight patients) than in the stable group (one of 27 patients). All of five patients harboring both karyotypic evolution and an N-ras mutation showed concomitant disease progression to overt leukemia or refractory anemia with excess of blasts in transformation (RAEB-T). Two of four patients with either karyotypic evolution or N-ras mutation and six of 26 patients without any of these alterations also progressed to overt leukemia. Our results indicate that the accumulation of these genetic alterations is closely associated with leukemic transformation of MDS, although other genetic alterations may also play a key role in the remaining patients.
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PMID:N-ras mutation and karyotypic evolution are closely associated with leukemic transformation in myelodysplastic syndrome. 805 69

The endogenous endonucleases capable of producing nucleosomal-size DNA fragmentation are considered candidates of the key enzyme of apoptosis. We examined these activities in the nuclear fraction of non-adherent marrow mononuclear cells (NonAd-MNCs) from patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) using a nuclear autodigestion method. We detected Ca2+/Mg(2+)-dependent endonuclease activity in all samples examined. In contrast, Ca(2+)-independent activity with the ability to produce nucleosomal-size DNA fragmentation was found only in samples from a proportion of patients with MDS (12 of 26 consecutive cases) and all the patients with AML (n = 6), but not in the samples from control group patients (n = 10). This activity was correlated with the percentage of bone marrow (BM) blast cells to some extent. Although the levels of these endogenous endonuclease activities seem not to be correlated directly with the susceptibility of the cells to apoptosis, we postulate that the Ca(2+)-independent endonuclease activity may be associated with apoptosis and/or cell proliferation. Further follow-up study of these patients may be meaningful to clarify the prognostic significance of the Ca(2+)-independent endonuclease activity in patients with MDS.
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PMID:High levels of Ca(2+)-independent endonuclease activity capable of producing nucleosomal-size DNA fragmentation in non-adherent marrow mononuclear cells from patients with myelodysplastic syndromes and acute myelogenous leukemia. 855 41

We examined the endonuclease activity capable of inducing internucleosomal DNA fragmentation in hematopoietic cells. Mg(2+)-dependent nuclease activity was high in hematopoietic progenitor cells and the activity decreased with myeloid or erythroid differentiation. This was the case in MDS as well as in normal hematopoiesis. In contrast, Ca2+/Mg(2+)-dependent nuclease activity varied widely in the samples from MDS and the possibility was indicated that the activity of Glycophorin A+ cells was related to the degree of anemia. We also investigated DNA strand breaks in bone marrow samples from 16 patients with MDS and 10 with other diseases by an in situ end labeling (ISEL) technique. The reactivity in ISEL tended to increase parallel to disease progression of MDS. The high ISEL-positivity was also observed in some samples from patients with MPD and other diseases. Though ISEL is a useful technique for quantification of apoptosis, our results suggested that MDS cells with ISEL positive staining are not necessarily in the process of apoptosis.
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PMID:[Apoptosis in MDS]. 877 68

Endonucleases capable of producing internucleosomal DNA cleavage are one of the key enzymes in apoptosis. We examined endonuclease activities contained in nuclei of CD34+ and erythroid cells in the bone marrow (BM) from 12 patients with the myelodysplastic syndromes. The levels of Mg(2+)-dependent and acidic endonucleases showed little changes as compared with those from normal BM. By contrast, the level of Ca2+/Mg(2+)-dependent endonuclease was appreciably higher in MDS erythroid cells than normal counterparts, although the activity varied markedly in CD34+ and erythroid cells. Our results suggested that Ca2+/Mg(2+)-dependent endonuclease is related to ineffective erythropoiesis in MDS.
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PMID:Ca2+/Mg(2+)-dependent endonuclease in marrow CD34 positive and erythroid cells in myelodysplasia. 937 80

Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an approximately 3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.
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PMID:An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity. 2103 Mar 22

FLT3 is one of the most frequently mutated genes in acute myeloid leukemia. Previous studies have reported FLT3 mutation in as many as 9.2% of myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), as well as in chronic myelogenous leukemia, that are negative for the JAK2 V617F gene mutation; no FLT3 mutation has been found in JAK2-positive MPNs, suggesting that the mutations are mutually exclusive. The goal of our study is to evaluate the mutational status of the FLT3 gene in patients with an MPN or MDS/MPN, in correlation with the JAK2 mutational status. Patient specimens were retrospectively identified on the basis of MPN or MDS/MPN diagnosis and JAK2 analysis from February 2006 to December 2011. FLT3 mutation analysis was performed on DNA extracted from 152 patients using polymerase chain reaction amplification and analysis of amplicons by gel electrophoresis for internal tandem duplication mutations and by restriction endonuclease digestion fragment analysis for the D835 point mutation. FLT3 mutation analysis was performed on 90 cases of JAK2-negative MPN or MDS/MPN and 62 cases of JAK2-positive MPN. One FLT3 internal tandem duplication mutation was identified in the JAK2-negative group (1.1%), and none were identified in the JAK2-positive group, confirming the absence of FLT3 mutations in JAK2-positive specimens. The FLT3-positive MPN patient was diagnosed with MPN, unclassifiable, and was later found to have myeloid sarcoma; thus, FLT3 mutation was not seen in the usual types of MPN in our series. Our result of 1.1% FLT3 mutations in JAK2-negative MPN and MDS/MPN cases is lower than the 9.2% previously reported.
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PMID:FLT3 mutations in myeloproliferative neoplasms: the Beaumont experience. 2384 42