Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myeloperoxidase (MPO) is found exclusively in the azurophilic granules (primary lysosomes) of normal myelomonocytic cells. Cytochemical staining for MPO activity is used clinically to distinguish myeloid from lymphoid leukemias. We studied the expression of MPO at the RNA and protein level in 140 continuous human leukemia-lymphoma cell lines using classical cytochemistry, immunofluorescent staining with a specific monoclonal antibody, Northern blot analysis, and a reverse transcription-polymerase chain reaction (RT-PCR) amplification assay. Seventy-eight lymphoid leukemia, myeloma, and lymphoma cell lines were negative; only 3 pre-B-acute lymphoblastic leukemia (ALL) cell lines were MPO-positive. Two of these MPO-positive pre-B-ALL cell lines showed a trace expression after RT-PCR and Southern blotting corresponding to 4% to 6% of the transcripts found in other positive myeloid cell lines. The third pre-B-ALL cell line was positive in Northern blots and cytochemical/immunofluorescent staining; however, only few cells were weakly positive in the latter assay. Although 15 of 59 cell lines assigned to the myeloid, monocytic, megakaryocytic, or erythroid lineages were MPO-positive in Northern blots, those 15 and 13 additional cell lines showed bands of mRNA after RT-PCR. MPO protein was detected in all 16 Northern-positive cell lines; on the other hand, there were 4 cell lines that were protein-positive, but Northern-negative. Differentiation induced by protein kinase C activators 12-O-tetradecanoylphorbol 13-acetate and Bryostatin 1 or by all-trans retinoic acid was associated with a decrease in MPO mRNA in all 7 initially positive cell lines studied, even leading to the complete absence of transcripts, but the enzymatic activity of the differentiated cells was only slightly less than that of unstimulated cells. MPO expression could not be induced in 10 initially negative cell lines. The half-life of MPO mRNA was found to be about 6 hours and was not shortened by prior exposure of the cells to the differentiation-inducing agents. These results confirm that MPO expression is mainly associated with myelomonocytic cells, but also underline the notion that MPO cannot be used as an absolutely lineage-specific marker for the distinction of leukemic cells. MPO can be used as an excellent parameter to characterize the various stages of normal and induced differentiation.
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PMID:Myeloperoxidase: expression and modulation in a large panel of human leukemia-lymphoma cell lines. 839 12

Myeloperoxidase (MPO) is an enzyme which is exclusively expressed in immature myeloid cells with downregulation of gene expression occurring during granulocytic maturation. Levels of MPO RNA, protein, and enzyme activity differ, usually in a concordant fashion, among the various classes of acute leukemia and among different cases within a particular class. One portion of the gene thought to be involved in regulation of MPO expression is the proximal 5' flanking region. To determine if mutations in this putatively regulatory region of the MPO gene might be responsible for some of the differences in level of MPO expression among different cases or classes of acute leukemia, we compared the nucleotide sequence of this part of the gene from 16 patients with acute leukemia, with DNA from normal human bone marrow cells and selected other neoplasms and cell lines. The sequence of this regulatory region was found to be identical in cases of acute myeloid leukemia (AML) with tha of normal DNA except for a dA to dG transition in the Alu region, 463 bases upstream from the transcription start site. This base substitution was seen in almost all cases of AML studied, regardless of the level of MPO which they expressed. It was absent from normal human DNA obtained from various tissues, and cases of acute and chronic lymphocytic leukemia, carcinoma of lung, and most cell lines examined. The base substitution was also absent in a remission blood sample from one of the cases which showed the dA to dG transition in leukemic marrow, suggesting that the base substitution is a mutation rather than a polymorphism. Our results suggest that mutations in promoter or enhancer DNA are not an important cause of the differences in level of MPO gene expression seen among different cases or different classes of AML. However, the base substitution we have detected could potentially serve as a useful marker for detection of residual disease in patients with AML following treatment.
Leukemia 1993 Sep
PMID:Sequence comparison of putative regulatory DNA of the 5' flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells. 839 97

Myeloperoxidase (MPO) is an important component of the oxidative antibacterial defense system of granulocytes. Mammalian MPO gene expression has been most extensively studied in human and murine cells. Transcription of the human MPO gene appears to begin at a single initiation site and we have recently described the isolation and characterization of the corresponding human MPO promoter. On the other hand, MPO transcripts in murine myeloid cells show several distinct 5'-termini, suggesting the existence of multiple murine MPO promoters. However, significant levels of endogenous murine MPO promoter activity have not been demonstrated heretofore, although several murine MPO enhancers have been described. We now report the identification and preliminary functional characterization of four distinct murine MPO promoters. Sequence comparison of the human and murine MPO promoter regions reveals homologues of three out of four of these murine promoters within the human MPO gene. However, only one of these sites appears to be functionally active in human myeloid cells, possibly because of the interposition of Alu sequences between the putative promoter sites in the human gene.
Leukemia 1997 Jan
PMID:Identification and functional analysis of multiple murine myeloperoxidase (MPO) promoters and comparison with the human MPO promoter region. 900 23

Biosynthesis of 3 human granule proteins, myeloperoxidase, defensin and lysozyme, all present in azurophil granules, was investigated in normal bone marrow cells and in the promyelocytic cell line HL-60 to see whether differences in timing of biosynthesis could explain the well established differences in their subcellular localization in the mature neutrophil (targeting), and whether differences exist in the efficiencies by which granule proteins are retained in cells (sorting). Normal human bone marrow cells were separated into three bands by density gradient centrifugation. Band 1 contains band and segmented cells, band 2 mainly myelocytes, metamyelocytes and some band cells, and band 3 myeloblasts and promyelocytes in addition to megakaryocytes and proerythroblasts. Cells from these bands, as well as undifferentiated HL-60 cells, were pulsed with radiolabeled cysteine and methionine, and biosynthesis of granule proteins was subsequently evaluated by immunoprecipitation and quantified by phosphorimaging. Myeloperoxidase synthesis was maximal in cells from band 3 while defensin biosynthesis was maximal in cells from band 2. Lysozyme was synthesized in cells from all bands but was maximal in cells from band 2. These results are in agreement with our hypothesis that timing of biosynthesis determines the localization of individual granule proteins. While myeloperoxidase and defensins were efficiently retained in immature cells (band 3), a significant fraction of lysozyme was routed out of the cells, showing that differences exist in the sorting of granule proteins between constitutive and regulated secretion. In addition, defensin was less efficiently retained in cells from band 2 than from band 3, indicating that sorting mechanisms may depend on the stage of cell maturation.
Leukemia 1998 Nov
PMID:Timing, targeting and sorting of azurophil granule proteins in human myeloid cells. 982 55

Myeloperoxidase (MPO) is found in the azurophilic granules of normal myelocytic cells. Cytochemical staining for MPO activity is used clinically to distinguish myeloid from acute lymphoid leukemias (ALL). However, using a highly sensitive RT-PCR technique, it is possible to detect MPO mRNA in otherwise clear ALL. The significance of this finding remains poorly understood. We have extended our observations to a series of 57 patients with the primary diagnosis of ALL (46 patients tested at diagnosis and 11 cases at relapse). We identified 25 cases (43.8%) of MPO mRNA(+)/enzyme(-) ALL (17 B cell and eight T cell lineage). Expression of myeloid antigens (CD13 or CD33) were detected in nine of them, and remarkably, 18 cases (72%) displayed CD34. Of these 25 MPO mRNA(+) leukemias, 10 (40%) are Bcr-Abl positive (with P210 fusion transcript in five patients while the five remaining cases carried P190 transcript). Moreover, 11 of 16 myeloid negative cases were also negative for any type of Bcr-Abl and MLL rearrangement, indicating that MPO mRNA positivity is not either invariably related to that chromosomal abnormality or necessarily associated with the presence of other myeloid differentiation features. Interestingly, six of these 11 cases are T-ALL, suggesting the presence of some overlapping phase for T and myeloid lineage commitment. Taken together, these findings could suggest a separate biological disease with immature origin and bipotential differentiation capability, which involves B and T-ALL subtypes and should lead to new investigations regarding their prognostic impact.
Leukemia 1999 Feb
PMID:Genetic, phenotypic and clinical features of acute lymphoblastic leukemias expressing myeloperoxidase mRNA detected by RT-PCR. 1158 32

Acute Lymphoblastic Leukaemia (ALL) with intracytoplasmic inclusions is a rare and unusual subtype of acute leukaemia. Here we describe a case of ALL with intracytoplasmic inclusions in an adult female. These inclusions stained negative for Myeloperoxidase (MPO), Sudan Black E (SBB) and alpha-naphthyl acetate estarase (ANAE) and positive for Periodic Acid Schiff (PAS). This case is being presented for its unusual occurrence and to recognise the characteristics of this subtype of ALL to avoid a misdiagnosis of AML.
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PMID:Acute lymphoblastic leukaemia with giant intracytoplasmic inclusions--a case report. 1134 20

Acute Lymphoblastic Leukaemia (ALL) with intracytoplasmic inclusions is a rare and unusual subtype of acute leukaemia. Here we describe a case of ALL with intracytoplasmic inclusions in an adult female. These inclusions stained negative for Myeloperoxidase (MPO), Sudan Black B (SBB) and Alpha-naphthyl acetate estarase (ANAE) and positive for Periodic Acid Schiff (PAS). This case is being presented for its unusual occurrence and to recognise the characteristics of this subtype of ALL to avoid a misdiagnosis of AML (Acute Myeloid Leukaemia).
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PMID:Acute lymphoblastic leukaemia with giant intracytoplasmic inclusion--a case report. 1188 36

Myeloperoxidase (MPO)-catalyzed one-electron oxidation of endogenous phenolic constituents (e.g., antioxidants, hydroxylated metabolites) and exogenous compounds (e.g., drugs, environmental chemicals) generates free radical intermediates: phenoxyl radicals. Reduction of these intermediates by endogenous reductants, i.e. recycling, may enhance their antioxidant potential and/or prevent their potential cytotoxic and genotoxic effects. The goal of this work was to determine whether generation and recycling of MPO-catalyzed phenoxyl radicals of a vitamin E homologue, 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC), by physiologically relevant intracellular reductants such as ascorbate/lipoate could be demonstrated in intact MPO-rich human leukemia HL-60 cells. A model system was developed to show that MPO/H(2)O(2)-catalyzed PMC phenoxyl radicals (PMC*) could be recycled by ascorbate or ascorbate/dihydrolipoic acid (DHLA) to regenerate the parent compound. Absorbance measurements demonstrated that ascorbate prevents net oxidation of PMC by recycling the phenoxyl radical back to the parent compound. The presence of DHLA in the reaction mixture containing ascorbate extended the recycling reaction through regeneration of ascorbate. DHLA alone was unable to prevent PMC oxidation. These conclusions were confirmed by direct detection of PMC* and ascorbate radicals formed during the time course of the reactions by EPR spectroscopy. Based on results in the model system, PMC* and ascorbate radicals were identified by EPR spectroscopy in ascorbate-loaded HL-60 cells after addition of H(2)O(2) and the inhibitor of catalase, 3-aminotriazole (3-AT). The time course of PMC* and ascorbate radicals was found to follow the same reaction sequence as during their recycling in the model system. Recycling of PMC by ascorbate was also confirmed by HPLC assays in HL-60 cells. Pre-loading of HL-60 cells with lipoic acid regenerated ascorbate and thus increased the efficiency of ascorbate in recycling PMC*. Lipoic acid had no effect on PMC oxidation in the absence of ascorbate. Thus PMC phenoxyl radical does not directly oxidize thiols but can be recycled by dihydrolipoate in the presence of ascorbate. The role of phenoxyl radical recycling in maintaining antioxidant defense and protecting against cytotoxic and genotoxic phenolics is discussed.
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PMID:Direct evidence for recycling of myeloperoxidase-catalyzed phenoxyl radicals of a vitamin E homologue, 2,2,5,7,8-pentamethyl-6-hydroxy chromane, by ascorbate/dihydrolipoate in living HL-60 cells. 1259 76

CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s(low) AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986-1999). Of those, 198 (28%) qualified as having CD65s(low) AML. Morphologically, CD65s(low) AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P=<0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s(low) than CD65s(high) AML (P=<0.0001). Myeloperoxidase was present in fewer CD65s(low) myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P=<0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s(low) AML patients were significantly older than CD65s(high) cases (P<0.0001). Furthermore, the incidence of CD65s(low) cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (P<0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s(low) and CD65s(high) AML. However, among patients >55 years of age, CD65s(low) AML had a decreased CR rate of 33 vs 44% in CD65s(high) AML (P=0.055). Thus, CD65s(low) AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.
Leukemia 2003 Aug
PMID:Low expression of the myeloid differentiation antigen CD65s, a feature of poorly differentiated AML in older adults: study of 711 patients enrolled in ECOG trials. 1288 41

Chromosomal abnormalities like monosomies and trisomies predispose to various malignancies, hematopoietic or non hematopoietic. Patients with Trisomy 21(Down's syndrome) are prone to acute leukemias during childhood, but congenital leukemia in such children is rare (17%) and should be differentiated from a similar condition -Transient Myeloproliferative Disorder (TMD) which does not necessitate any treatment other than follow up. We report a patient of Down's syndrome with TMD in neonatal period which had spontaneous remission at 3 weeks but later died of acute myeloid leukemia at 6 months. The blasts in our case during the TMD episode were Myeloperoxidase(MPO) positive unlike other cases of TMD reported in literature. To the best of our knowledge we have not come across a case of TMD (MPO positive) later progressing to leukemia in Indian literature. Hence we report this case.
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PMID:Congenital transient myeloproliferative disorder progressing to acute myeloid leukemia in Down's syndrome: a case report. 1547 Nov 29


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