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

High affinity receptors (VDR) for 1,25-dihydroxycholecalciferol (calcitriol) are expressed in HL60 human leukemia cells and in low numbers in peripheral blood lymphocytes (PBL). HL60 cells, expressing some characteristics of promyelocytes, can be induced to monocytoid differentiation by calcitriol. Specific nuclear translocation of [3H]calcitriol/VDR was examined after exposure of whole cells to 10(-9) M/l calcitriol in the presence and absence of a 500-fold excess of unlabeled ligand and subsequent isolation of nuclei. Specific nuclear translocation of [3H]calcitriol/VDR was found to be time dependent reaching a maximum of approximately 2100 binding sites/nucleus after 3 h of incubation in HL60 cells, whereas a maximum of approximately 310 binding sites/nucleus was found after 3 h in PBL. Pulse exposure of HL60 to radiolabeled hormone for 3 h followed by culture in medium without serum and calcitriol lead to nuclear retention of approximately 1600 radiolabeled VDR by 8 h and approximately 1000 VDR by 24 h. Radiolabeled VDR disappeared from the nuclear compartment with a halflife of approximately 30 min if cells were cultured with identical concentrations of unlabeled hormone after the pulse (pulse/chase-experiments). No difference of VDR retention in pulse and pulse/chase-experiments was seen in PBL, where VDR halflife was approximately 30 min. No specific translocation into the nuclear compartment was seen when isolated nuclei were incubated in [3H]calcitriol. Radiolabeled hormone/receptor complexes of nuclei isolated from cells exposed for 3 h to radiolabeled hormone--in contrast to identical experiments with intact cells--did not disappear from the nuclear compartment upon incubation of nuclei with identical concentrations of the unlabeled compound. The activity of DNA relaxing enzymes (e.g. topoisomerases I and II) in nuclear extracts was measured using a PBR 322-relaxation-assay. Enhanced overall enzyme activity was found in nuclear extracts by 1 h after incubation with calcitriol (final ethanol concentration 0.0001% v/v) in HL60 and PBL. The enhanced activity disappeared after 2 h in PBL, whereas it was still enhanced by 4 h in HL60. No effect was seen in ethanol treated controls. We conclude that a specific nuclear translocation mechanism exists for calcitriol in both cell types examined, most likely due to translocation of receptor proteins after hormone binding. Translocated hormone/receptor complexes compete for a limited number of specific nuclear binding sites. Enhanced activity of topoisomerases in nuclear extracts upon translocation of VDR might reflect interaction of both within the nuclear compartment, thus initiating DNA-unwinding, a prerequisite of transcription initiation.
 ...
PMID:Kinetics of nuclear translocation and turnover of the vitamin D receptor in human HL60 leukemia cells and peripheral blood lymphocytes--coincident rise of DNA-relaxing activity in nuclear extracts. 131 93

Hypercalcaemia occurs in up to 80% of patients with adult T-cell leukaemia-lymphoma (ATLL) associated with human T-cell leukaemia virus-1 infection. Elevated serum levels of 1,25-dihydroxycholecalciferol, implicated in the pathogenesis of hypercalcaemia in lymphoma, and of parathyroid hormone-related protein (PTHrP), which is associated with hypercalcaemia of several solid malignancies, were demonstrated in a patient with ATLL hypercalcaemia. Treatment with bisphosphonates reduced the serum calcium but had no significant effect on the serum PTHrP levels. This case supports recent in vitro evidence for enhanced PTHrP expression in ATLL tumour cells and suggests that more than one tumour cell product may be involved in the pathogenesis of ATLL hypercalcaemia.
 ...
PMID:Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma. 148 May 40

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3)-induced differentiation of HL-60 leukemia cells is accompanied by a number of cellular changes including regulation of oncogene expression and induction of terminal differentiation. We investigated the mechanism by which 1,25-(OH)2D3 induces these changes. We detected 10 nuclear phosphoproteins, designated p66, p45, p36, p33, p32, p27, p22, p19, p18 and p17, that show alterations in phosphorylation within 6-40 h of 1,25-(OH)2D3 treatment. When phosphorylation reactions were performed with isolated nuclei (in vitro), three of these proteins were phosphorylated in a calcium and phospholipid dependent manner: p66, p36, and p19 P66 was phosphorylated in response to 1,25-(OH)2D3 and purified in a manner similar to that used for nuclear lamins. Western blot analysis of 2-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels confirmed its identity as lamin B. Phosphorylation of p17 and p18 decreased following 1,25-(OH)2D3 treatment. We separated p17 and p18 by SDS-PAGE and obtained N-terminal amino acid sequence to identify these phosphorproteins as histones H2b and H3, respectively. P19 and p22 were both DNA-cellulose binding proteins whose phosphorylation was altered by 1,25-(OH)2D3 treatment. Increased phosphorylation of p27 was detected using 2-dimensional SDS-PAGE. Phosphorylation of nuclear proteins in the intact cell (in vivo), revealed increases in p66, p45, p36, and p33 phosphorylation and a decrease in p17 phosphorylation following 1,25-(OH)2D3 treatment. We detected an increase in phosphorylation of p32, which was extracted with salt from nuclei and migrated on SDS-PAGE similar to histone H1. Thus, we have identified 1,25-(OH)2D3-sensitive nuclear phosphoproteins, including lamin B and several histones. We have also detected and characterized several less abundant nuclear DNA binding phosphoproteins whose phosphorylation was affected by 1,25-(OH)2D3.
 ...
PMID:Identification of lamin B and histones as 1,25-dihydroxyvitamin D3-regulated nuclear phosphoproteins in HL-60 cells. 155 89

1,25-Dihydroxyvitamin D3 induces the human promyelocyte leukemia cell line, HL-60, to differentiate into macrophages/monocytes via a steroid-receptor mechanism. This system is a relevant one for an investigation of the molecular mechanism of 1,25-dihydroxyvitamin D3. We have now examined the effect of 1,25-dihydroxyvitamin D3 on the induction of 1,25-dihydroxyvitamin D3- and 25-hydroxyvitamin D3-24-hydroxylase activities in HL-60 cells. The hydroxylase activities were measured by a periodate-based assay, which was validated by comparison with well-established HPLC analysis. HPLC analysis also suggested that 1,25-dihydroxyvitamin D3 induces a 23-hydroxylase in addition to the 24-hydroxylase. 1,25-Dihydroxyvitamin D3- and 25-hydroxyvitamin D3-24-hydroxylase activities were stimulated as early as 4 h after the addition of 10(-7) M 1,25-dihydroxyvitamin D3 and became maximal by 24 h. 1,25-Dihydroxyvitamin D3 stimulated both activities in a dose-dependent manner up to 10(-6) M. The Km of 24-hydroxylase for 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 were 2 x 10(-8) M and 5.2 x 10(-7) M, respectively. Cycloheximide (5 microM) inhibited 1,25-dihydroxyvitamin D3-mediated stimulation of 24-hydroxylase activity. Other differentiation inducers, such as retinoic acid and phorbol ester, did not induce either activity. 1,25-Dihydroxyvitamin D3-24-hydroxylase in HL-60 mitochondria was solubilized with 0.6% cholate and reconstituted with NADPH, beef adrenal ferredoxin, and beef adrenal ferredoxin reductase, each component being essential for 24-hydroxylase activity. These results strongly suggest that the 24-hydroxylase in HL-60 cells is a three-component cytochrome P450-dependent mixed-function oxidase.
 ...
PMID:Characteristics of the 25-hydroxyvitamin D3- and 1,25-dihydroxyvitamin D3-24-hydroxylase(s) from HL-60 cells. 184 19

The monoblastlike leukemia cell line, U-937, is induced to differentiate into monocytelike cells by incubation with 200-500 U/ml of recombinant human immune interferon (IFN-gamma) judging from capacity to reduce nitroblue tetrazolium. At least an additive differentiation-inducing effect was found between IFN-gamma and 1-100 nM retinoic acid (RA). A marked synergistic differentiation-inducing effect was found between IFN-gamma and 0.1-1.0 nM 1 alpha,25-dihydroxycholecalciferol (1,25[OH]2D3). It is also shown that U-937 can be primed for differentiation by treatment for approximately one day with 1,25(OH)2D3 followed by exposure to IFN-gamma. Priming of these cells does not depend on the normal rate of RNA synthesis, as it occurs even better in the presence of cordycepin, suggesting that a decrease in RNA synthesis favors IFN-induced differentiation. Actually, the addition of cordycepin during initial incubation with IFN increased the subsequent response to IFN-gamma (and also to RA and 1,25[OH]2D3). These results, indicating that combinations of IFN-gamma and either RA or 1,25(OH)2D3 induce differentiation of U-937, may be of importance in combination biotherapy of leukemia.
 ...
PMID:Combinations of interferon-gamma and retinoic acid or 1 alpha, 25-dihydroxycholecalciferol induce differentiation of the human monoblast leukemia cell line U-937. 241 82

The human monoblast leukemia line U937 is growth inhibited and induced to express various characteristics of mature monocytes by lymphokines (LK) and other cytokines. Previous experiments have shown that interferon-gamma (IFN-gamma) is responsible for some but not all of the differentiation-inducing effects on U937. To determine the variety and specificity of activity, the following factors were studied: phytohemagglutinin-induced LK that contained IFN-gamma (100 units/ml); purified IFN-gamma; human colony-stimulating factor 1 (CSF-1); and conditioned medium(a) (CM) from the human bladder carcinoma cell line 5637 and the hepatoma cell line SK-HEP. LK preparations contained no colony-stimulating activity, whereas CM from 5637 and SK-HEP both contained granulocyte-macrophage CSF (3000 to 4000 units/ml) but no IFN activity. IFN-gamma is the major immunoglobulin G Fc receptor-inducing species within lymphokine, since anti-interferon-gamma antibody inhibited most of this activity. Other sources of Fc receptor-inducing activity were CM from SK-HEP and 5637 cell lines. Human CSF-1 when tested up to 800 units/ml was inactive for Fc receptor induction. LK induced the chemotactic peptide receptor, but this induction was due to factors other than IFN-gamma as anti-IFN-gamma antibody did not inhibit the induction, and purified IFN-gamma at a dose equivalent to that found in LK (100 units/ml) had no activity in the assay. SK-HEP and 5637 CM had strong chemotactic peptide receptor-inducing activity, but human CSF-1 was inactive up to 800 units/ml. Peroxide production after stimulation with phorbol myristic acid could be induced by LK, LK with anti-IFN-gamma antibody, 5637, and SK-HEP treatment. IFN-gamma (100 units/ml) and CSF-1 (800 units/ml) were ineffective. Peroxide production was induced by IFN-gamma at concentrations above 1000 units/ml. The inducibility of several enzymatic activities was determined as additional measures of maturation. N-Acetylglucuronidase was induced, for example, by LK, IFN-gamma, 5637 CM, and phorbol myristic acid. Alkaline phosphatase was induced by LK, IFN-gamma, dexamethasone, and phorbol myristic acid. 1,25-Dihydroxycholecalciferol was also examined and could induce most of the maturational markers examined. The results demonstrate that non-IFN cytokines from several sources have profound differentiation-inducing effects on monoblast leukemia cells in a pattern different from that of IFN-gamma.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Distinct activities of interferon-gamma, lymphokine and cytokine differentiation-inducing factors acting on the human monoblastic leukemia cell line U937. 298 Nov 61

Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for 1-6 days with 0.03-30 microM delta 9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana. After a 2-day or longer treatment, 2- to 5-fold increases were found in the percentages of cells exhibiting reactivity with either the murine OKM1 monoclonal antibody or the Leu-M5 monoclonal antibody, staining positively for nonspecific esterase activity, and displaying a promonocyte morphology. The increases in these differentiation markers after treatment with 0.03-1 microM THC were dose dependent. At this dose range, THC did not cause an inhibition of cell growth. The THC-induced cell maturation was also characterized by specific changes in the patterns of newly synthesized proteins. Pronounced among these changes was an increase in the synthesis of at least 10 proteins that are found abundantly in monocytes. The THC-induced differentiation did not, however, result in cells with a highly developed mature monocyte phenotype; the THC-treated cells failed to exhibit other monocyte markers such as attachment to the surface of tissue culture dishes or morphological maturation beyond the promonocyte stage. However, treatment of these "incompletely" matured cells with either phorbol 12-myristate 13-acetate or 1 alpha,25-dihydroxycholecalciferol, which are inducers of differentiation in myeloid leukemia cells (including ML-2 cells), produced cells with a mature monocyte morphology. Two other cannabinoids, cannabidiol and cannabinol, which were more cytotoxic than THC at comparable doses, also caused an increase in the expression of maturation markers, but at doses higher than those required for THC. The ML-2 cell system described here may be a useful tool for deciphering critical biochemical events that lead to the cannabinoid-induced "incomplete" cell differentiation of ML-2 cells and other related cell types. Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells.
 ...
PMID:Cannabinoids induce incomplete maturation of cultured human leukemia cells. 303 49

A patient with acute monocytic leukemia and fibrosis presented with severe hypocalcemia producing tetany, myocardial failure, and ventricular tachycardia with torsades de pointes configuration. Hypophosphatemia, hypomagnesemia, an elevated alkaline phosphatase level, and osteosclerosis were also present. Bone marrow biopsy samples showed fibrosis and thickened bony trabeculae lined with large osteoblasts. Tetracycline labeling showed an increased rate of calcification. Complete remission of the leukemia and fibrosis was achieved with a single 3-week course of low-dose cytarabine and hydroxyurea, with resolution of the hypocalcemia and hypophosphatemia. Calcitriol and etidronate disodium were also administered. The calculated left ventricular ejection fraction increased from 15% to 55% with correction of the hypocalcemia. The hypocalcemia and hypophosphatemia in this patient probably resulted from accelerated bone formation stimulated by the leukemic cells. The high dose of calcitriol that this patient received may have contributed to the remission of the leukemia.
 ...
PMID:Accelerated bone formation causing profound hypocalcemia in acute leukemia. 346 37

Work based on immortalised leukemic cell lines indicates that the maturation arrest in leukemia can be reversible. Successful differentiation induction would mean restoring the link between proliferation and differentiation. Human cell lines such as the promyelocytic HL-60 and the monoblastic U-937 can be induced to mature by incubation with a wide variety of agents, e.g. phorbol diesters, retinoic acid and 1,25-dihydroxycholecalciferol. In addition, mitogen-stimulated lymphocytes and some T-lymphocyte lines produce a polypeptide called the differentiation-inducing factor (DIF), which mediates maturation of HL-60 into macrophage-like cells with resulting proliferation inhibition. DIF also displays a primary growth inhibitory effect on certain subclones of the cell lines as well as on fresh clonogenic cells from patients with acute myeloid leukemia and on normal granulocyte-macrophage progenitors. Our data indicate that there is more than one way to induce differentiation in leukemia but final common pathways may exist. Complementary, synergistic, maturation effects are seen between some agents, which may become of clinical utility.
 ...
PMID:Differentiation induction in myeloid leukemic cells. 346 43

The murine myelomonocytic leukemia cell line WEHI-3B D+, which differentiates in response to granulocyte colony stimulating factor (G-CSF), can also be induced to differentiate into monocyte-macrophages by phorbol myristate acetate (PMA) treatment, whereas the WEHI-3B D- subline, which is unresponsive to G-CSF and PMA, can be induced to differentiate to granulocytes as well as monocytes by 1,25-dihydroxycholecalciferol [1,25-(OH)2 D3], the biologically active metabolite of vitamin D3. A newly developed variant of the WEHI-3B D+ line, named WEHI-3B D+ G, which was responsive to G-CSF but not to PMA, was also differentiated to granulocytes by 1,25-(OH)2 D3. Although vitamin D3 has been reported to induce macrophage differentiation in responsive tumor cells, this is the first demonstration that 1,25-(OH)2 D3 can induce granulocyte differentiation. In both differentiation pathways, cessation of cellular proliferation accompanies changes in morphologic and cytochemical properties of the cells. This suggests that leukemic cell lines unresponsive to differentiation agents acting at the cell surface retain their ability to differentiate in response to agents that do not act via the plasma membrane such as 1,25-(OH)2 D3, which has cytosolic/nuclear receptors. Vitamin D3 could act through different cellular pathways inducing differentiation or by bypassing only the first step of a common differentiation cascade used by agents with cell surface receptors such as CSF. These results suggest that low doses of 1,25-(OH)2 D3 may be useful in combination with hemopoietic growth factors (CSFs) as therapeutic agent to induce leukemic cell differentiation in vivo.
 ...
PMID:1,25-Dihydroxycholecalciferol-induced differentiation of myelomonocytic leukemic cells unresponsive to colony stimulating factors and phorbol esters. 349 Oct 83


1 2 3 4 Next >>