Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to obtain more precise information about the purine biosynthetic pathway in human blood cells. 5'phosphoribosyl-l-pyrophosphate (PP-ribose-P) amidotransferase was found in cell-free extracts from all leukemic cells and normal lymphocytes and therefore these cells could synthesize the first intermediate of the purine-de-novo-synthesis. Normal leucocytes, erythrocytes and bone marrow cells lack this enzyme system and have an absolute requirement for externally supplied purines via salvage pathway. Leukemic blast cells show different enzyme activities independent of their cell count. Kinetic studies with the crude enzymes showed sigmoidal substrate velocity curves for PP-ribose-P, whereas glutamine shows hyperbolic kinetics. The leukemic cell enzymes from all four donor types (ALL, CLL, AML and CML) are rapidly saturated with low concentrations of PP-ribose-P and less inhibited by the physiological feedback inhibitor, adenosine 5'monophosphate. The crude enzymes of normal spleen lymphocytes and leukemic cells were further purified (10 to 15-fold) and substrate velocity curves for PP-ribose-P and glutamine show now hyperbolic kinetics and double reciprocal plots were linear with and apparent Km for PP-ribose-P of 0.14 mM and for glutamine 2.0 mM. In the presence of different concentrations of AMP, the PP-ribose-P substrate velocity plot changed from a hyperbolic to a sigmoidal curve; no difference in the degree of the inhibition between both partially purified enzymes (normal spleen lymphocytes and leukemic cells from all four donor types) could now be observed.
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PMID:Purine nucleotide synthesis in normal and leukemic blood cells. 64 99

Pharmacologic differentiation of the promyelocytic leukemia HL60 is associated with an increase in cellular tyrosine phosphatase activity. We asked (a) if this increase might, at least in part, be due to changes in a transmembranous protein-tyrosine phosphatase, CD45; and (b) if CD45 changes similarly in other differentiating leukemias. Differentiation of HL60, several chronic myelogenous leukemias, a monocytic leukemia (THP-1), and a monoblastoid leukemia (U-937) could be induced by phorbol ester, 1,25-dihydroxy vitamin D3, dimethyl sulfoxide, or cyclic AMP analogues. This differentiation was associated with a marked increase in (a) total cellular tyrosine phosphatase activity (2-4-fold as measured by the ability to dephosphorylate a tyrosine-phosphorylated peptide); (b) CD45-specific tyrosine phosphatase activity (2-4-fold); (c) CD45 cell surface expression by flow cytometry (2-5-fold); (d) synthesis of both exon B-dependent M(r) 205,000 and exon ABC- M(r) 185,000 CD45 proteins, as revealed by immunoprecipitation with antisera specific for CD45 isoforms. Both isoforms have enhanced electrophoretic mobility when isolated from the differentiated cells. This enhanced mobility did not appear to be due to decreased stoichiometry of CD45 phosphorylation on serine/threonine residues. Interestingly, 12-O-tetradecanoylphorbol-13-acetate transiently reduced CD45 protein-tyrosine phosphatase activity in the chronic myelogenous leukemia cell RWLeu4 without altering the CD45 amount (as measured by cell surface immunofluorescence). Modulation of CD45 tyrosine phosphatase activity (and protein levels) may play a role in differentiation or in maintaining cells in a nonproliferative state or may represent a phenotypic marker of differentiation.
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PMID:Differentiation-induced changes in protein-tyrosine phosphatase activity and commensurate expression of CD45 in human leukemia cell lines. 153 52

A transcriptional enhancer has been mapped to a region 5.5 kilobases 3' of the C beta 2 gene in the human T-cell receptor (TCR) beta-chain locus. Transient transfections allowed localization of enhancer activity to a 480-base-pair HincII-XbaI restriction enzyme fragment. The TCR beta enhancer was active on both the minimal simian virus 40 promoter and a TCR beta variable gene promoter in both TCR alpha/beta + and TCR gamma/delta + T cells. It displayed significantly less activity in Epstein-Barr virus-transformed B cells and K562 chronic myelogenous leukemia cells and no activity in HeLa fibroblasts. DNA sequence analysis revealed that the enhancer contains a consensus immunoglobulin kappa E2 motif, as well as an AP-1-binding site and a cyclic AMP response element. DNase I footprint analyses using Jurkat T-cell nuclear extracts allowed the identification of five nuclear protein-binding sites, T beta 1 to T beta 5, within the enhancer element. Deletion and in vitro mutagenesis studies demonstrated that the T beta 2- and T beta 3- and T beta 4-binding sites are each required for full transcriptional enhancer activity. In contrast, deletion of the T beta 1- and T beta 5-binding sites had essentially no effect on enhancer function. Electrophoretic mobility shift assays demonstrated that TCR alpha/beta + and TCR gamma/delta + T cells expressed T beta 2-, T beta 3-, and T beta 4-binding activities. In contrast, non-T-cell lines, in which the enhancer was inactive, each lacked expression of at least one of these binding activities. TCR alpha and beta gene expression may be regulated by a common set of T-cell nuclear proteins in that the T beta 2 element binding a set of cyclic AMP response element-binding proteins that are also bound by the T alpha 1 element of the human TCR alpha enhancer and the decamer element present in a large number of human and murine TCR beta promoters. Similarly, the T beta 5 TCR beta-enhancer element and the T alpha 2 TCR alpha-enhancer element bind at least one common T-cell nuclear protein. Taken together, these results suggest that TCR beta gene expression is regulated by the interaction of multiple T cell nuclear proteins with a transcriptional enhancer element located 3' of the C beta 2 gene and that some of these proteins may be involved in the coordinate regulation of TCR alpha and beta gene expression.
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PMID:Identification and functional characterization of the human T-cell receptor beta gene transcriptional enhancer: common nuclear proteins interact with the transcriptional regulatory elements of the T-cell receptor alpha and beta genes. 214 10

We tried to treat 13 patients with myelodysplastic syndromes (MDS), leukemias and myeloproliferative disorders, with alfacalcidol for their hematological improvement. Eight of them had MDS, 2 acute leukemia (M3, M4), 1 chronic myelogenous leukemia and 2 primary myelofibrosis. All patients were untreated except for 3 patients (PASA, RAEB, AML-M4) who had been treated with mepitiostane, prednisolone and BH.AC-AMP regimen, respectively, prior to alfacalcidol therapy. All patients received alfacalcidol orally for at least one month. The dosage of alfacalcidol ranged from 0.25 to 10 micrograms/day, and the medicine was administrated intermittently when the dosage exceeded 6 micrograms/day to prevent hypercalcemia. The therapeutic effectiveness of alfacalcidol was evaluated according to a criteria by Koeffler (Cancer Treat Rep 69: 1399, 1985) with minor modifications. Three patients (PASA, RAEB, CMML) showed partial response, 3 (RAEB, RAEB in T, AML-M4) minor response and rest of the patients did not respond. The hematological improvement of 6 responders was transient (from 1 to 2 months), however, one patient (PASA) is still responding to alfacalcidol therapy (0.25 microgram/day) for over 12 months. The dysplastic features of hemopoietic cells in the bone marrow showed no noticeable change during the hematological improvement in these responders, suggesting the improvement was obtained as a result of alteration in the proliferation or differentiation of neoplastic clone. None of 13 patients developed hypercalcemia. One patient (AML-M4) became excitable on high dose alfacalcidol (10 micrograms/day). In conclusion, alfacalcidol therapy is effective in some patients with MDS or leukemias and appears worthy especially in the clinical state in which chemotherapy is not indicated.
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PMID:[Therapeutic effectiveness of vitamin D3 in patients with myelodysplastic syndromes, leukemias and myeloproliferative disorders]. 271 94

A 43-year-old male patient with hypercalcemia and osteolytic lesions complicating chronic myelogenous leukemia is presented. Extramedullary myeloid blastic crisis was diagnosed by the histological finding of the specimen biopsied from a osteolytic lesion in the right femur. As the serum levels of parathyroid hormone, 1,25 (OH)2 vitamin D, prostaglandin E2 and interleukin 1, and the urinary excretion of cyclic AMP were all normal, it was considered that the hypercalcemia was attributed to the bone destruction by the invasion of leukemic myeloblasts.
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PMID:Hypercalcemia associated with osteolytic lesions in the extramedullary blastic crisis of chronic myelogenous leukemia: report of a case. 281 52

A 38-year-old woman with megakaryoblastic chronic myelocytic leukemia (CML) crisis developed recurrent episodes of severe hypercalcemia, manifested by nausea and vomiting and later by dyspnea and hypoxia. The levels of serum parathyroid hormone and serum and urine cyclic AMP were normal. Autopsy revealed widespread metastatic calcifications in various organs, including the lungs. The case suggests that hypercalcemia complicating blast crisis of CML is not related to blast cell phenotype, can cause severe pulmonary malfunction, and is a terminal event. The hypercalcemia most probably resulted from bone resorption, either directly by the megakaryoblasts or by secretion of osteolytic substances.
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PMID:Hypercalcemia complicating a megakaryoblastic crisis of chronic myelocytic leukemia. 316 88

Sixteen children with refractory hematological malignancies were treated with a combination of BH.AC, aclacinomycin-A, 6-MP and predonisolone (BH-AC.AMP protocol). They were ALL(6), ANLL(8), CML(1) and NHL(1). The CR ratio was 17% in ALL, 50% in ANLL, and blast crisis of CML was treated successfully but NHL failed in the induction remission. Major complications were vomiting, nausea, gastrointestinal bleeding, hematuria and hemorrhagic cystitis. More than 10 days or 120 mg/m2 administration of aclacinomycin-A was thought to induce more severe side effects.
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PMID:[BH-AC.AMP protocol in the treatment of refractory childhood acute leukemia]. 317 40

Protein kinase activities and cyclic AMP binding capacity were investigated in human peripheral blood cells from leukemic patients and normal controls. Using [gamma 32P] ATP as phosphoryldonor, the phosphorylating activities were not found to be significantly different in either normal or leukemic cells when measured on both artificial basic and acidic substrates. In contrast, the GTP-dependent casein kinase activity, CK2, which is almost undetectable in normal granulocytes, was markedly increased in highly proliferating myeloblastic cells from patients with acute myelogenous leukemia (AML) or with chronic myelogenous leukemia in blastic crisis (BC-CML). Levels of endogenous phosphotyrosine were not higher in leukemic cells than in normal peripheral lymphocytes or granulocytes. Finally, cAMP binding capacity was found to be increased in several types of proliferating leukemic cells, due to a higher amount of the R1-type regulatory subunit of the cAMP-dependent protein kinases. Specific patterns of cAMP binding proteins observed in the different types of normal blood cells were rather blurred in leukemic cells. In conclusion, modifications observed in human leukemic cells seem to be more related to proliferation or blockage in normal differentiation than to their cellular origin.
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PMID:Protein kinases in human leukemic cells. 386 3

Hypercalcemia was associated with osteolytic bone lesions in a 60-year-old woman with chronic myelogenous leukemia in the accelerated phase. Using highly specific antisera to parathyroid hormone, radioimmunoassays disclosed elevated levels of carboxyl-terminal (53-84) and intermediate (44-68) fragments. In addition, concomitant variations of serum calcium level and leukocyte counts, increased urinary c-AMP excretion, morphological integrity of parathyroid glands, and absence of bone resorbing activity in myeloblast culture supernatants are consistent with the hypothesis that the humoral hypercalcemia was due to the excessive production of PTH. This production may have been ectopic, although no PTH secretion was demonstrated in myeloblast culture supernatants.
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PMID:Hypercalcemia in chronic myelogenous leukemia: evidence for excessive parathyroid hormone secretion. 386 73

Cyclic cytidine 3':5'-monophosphate (cyclic CMP), cyclic guanosine 3':5'-monophosphate (cyclic GMP), and cyclic adenosine 3':5'-monophosphate (cyclic AMP) contents of leukocytes and urines of leukemic patients have been investigated. We have studied four types of leukemia: acute myeloblastic leukemia; chronic myelocytic leukemia; acute lymphoblastic leukemia; and chronic lymphocytic leukemia. As controls, the cyclic nucleotide content of leukocytes and urines of healthy volunteers and patients with solid tumors selected for their normal hemogram has been determined. It has also been measured in phytohemagglutinin-stimulated lymphocytes. Our data show that: (a) the concentration of cyclic CMP is always lower than that of cyclic GMP or cyclic AMP; (b) in urines, the concentrations of the three nucleotides are higher in patients than in healthy volunteers, the greatest differences being observed between the cyclic CMP concentrations of acute leukemia patients and controls; and (c) in white blood cells, cyclic AMP concentration is lower in leukemic than in normal cells. The cyclic GMP concentration is the same everywhere except in monoblastic cells and leukocytes from solid tumor patients. High cyclic CMP levels are associated only with acute leukemia, whether myeloblastic, monoblastic, or lymphoblastic, a fact which suggests that cyclic CMP could be a biochemical marker of hematopoietic stem cell malignancy.
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PMID:Relationship between the levels of cyclic cytidine 3':5'-monophosphate, cyclic guanosine 3':5'-monophosphate, and cyclic adenosine 3':5'-monophosphate in urines and leukocytes and the type of human leukemias. 626 79


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