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)

The expression of the newly described human retinoic acid receptor alpha (RAR alpha) in six nonlymphoid and six lymphoid leukemia cell lines and nine freshly obtained samples of leukemia cells from patients with acute nonlymphoid leukemia was assessed by Northern blot analysis, using a full length cDNA clone of RAR alpha as probe. RAR alpha was expressed in all 12 cell lines and in all fresh leukemia samples as two major transcripts of 2.6 and 3.5 kb in size. Levels of RAR alpha expression and transcript sizes in retinoid-sensitive cells (such as HL60 or fresh promyelocytic leukemia cells) were not different from those in other samples. Moreover, expression of RAR alpha was not significantly modulated by exposure to cis-retinoic acid (cisRA) in either cisRA-responsive or unresponsive cells. By using a 3' fragment of the RAR alpha gene as a probe, we confirmed that the transcripts visualized did not represent the homologous RAR beta gene. RAR alpha appears to be expressed in most human leukemia cells regardless of the type of biologic response to retinoic acid.
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PMID:Expression of retinoic acid receptor alpha mRNA in human leukemia cells. 254 26

Retinoic acid receptor (RAR)-alpha mRNA expression was studied in a variety of myeloid leukemia cells with variable responsiveness to the induction of terminal differentiation by retinoic acid (RA). Cells from both the wild-type (wt), RA-responsive HL-60 promyelocytic leukemia cell line and a selected greater than or equal to 300-fold RA-resistant subline expressed approximately equal amounts of two RAR-alpha transcripts, 4.0 and 3.1 kb in size. In wt cells, the RAR-alpha did not change during induction of granulocyte differentiation by RA or macrophagic differentiation by 12-0-tetradecanoylphorbol-13-acetate (TPA). Relative to HL-60 cells, other cultured and fresh myeloid leukemia cells expressed 2.5-fold less to equal amounts of the RAR-alpha transcripts. The relative expression in six cases of acute promyelocytic leukemia (APL; two RA-responsive; one, previously treated with 13-cis-RA in vivo, equivocally RA-responsive) and one case of acute myelogenous leukemia (AML) with promyelocytosis (RA unresponsive) was 0.91 +/- 0.14 versus 0.53 +/- 0.14 for eight cases of nonpromyelocytic AML (p congruent to 0.001). Lymphoid leukemia cells expressed 2- to 5-fold less RAR-alpha mRNA. No qualitative variations in the mRNA transcripts were observed, although the 3.1 kb transcript was relatively decreased in three cases. The RAR-alpha gene was not amplified or detectably rearranged in any DNA source, although an apparent EcoRI restriction fragment length polymorphism was observed. It is concluded (a) that the steady-state level of RAR-alpha mRNA is not tightly correlated with natural responsiveness/unresponsiveness or, in some instances, acquired resistance to RA-induced differentiation and (b) that further studies are needed to determine if the mean 1.7-fold higher RAR-alpha mRNA level in APL cells could be an essential factor in the RA-responsiveness of APL cells, as primarily regulated at a different molecular level.
Leukemia 1989 Nov
PMID:Expression of retinoic acid receptor-alpha mRNA in human leukemia cells with variable responsiveness to retinoic acid. 255 72

A multidrug-resistant variant of the human HL-60 promyelocytic leukemia cell line (HL-60/MX2) has been isolated in vitro by subculturing these cells in progressively increasing concentrations of mitoxantrone. The MX2 cells are cross-resistant to etoposide, teniposide, bisantrene, dactinomycin, 4'-(9-acridinylamino)methanesulfon-m-anisidide, and the anthracyclines daunorubicin and doxorubicin but retain sensitivity to the Vinca alkaloids melphalan and mitomycin C. In addition, the MX2 cells display slight collateral sensitivity to bleomycin. Despite being 30-35-fold less sensitive to mitoxantrone, net [14C]mitoxantrone accumulation at 60 min was reduced by only 10% in the mitoxantrone-resistant cells compared to the parental line. Furthermore, at later time points, e.g., 120 and 180 min, mitoxantrone accumulation in the MX2 cells exceeded that in HL-60 cells by 8.5 and 6.4%, respectively. No significant differences were observed between the sensitive and resistant cell lines in the initial (first 60 s) accumulation of mitoxantrone, and only minor (3-6%) enhancement of mitoxantrone efflux was detected in the resistant cell type. Monoclonal antibodies to P-glycoprotein had no detectable reactivity with membrane vesicles from either the sensitive or resistant cell types as determined by standard immunoblotting techniques. The mitoxantrone-resistant cells displayed a reciprocal translocation [rcpt(1;3)-(q21;p23)] not found in the sensitive parent, but there were no demonstrable double minute chromosomes or homogeneous staining regions in cells from either line. Thus, these mitoxantrone-resistant human leukemia cells display many features which are atypical for the "classic" multidrug resistance phenotype and should provide a useful model for the study of multidrug resistance which is not mediated by P-glycoprotein.
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PMID:Multidrug resistance in mitoxantrone-selected HL-60 leukemia cells in the absence of P-glycoprotein overexpression. 256 72

We studied the differentiation of acute promyelocytic leukemia (APL) cells in 14 patients with APL. After the induction by retinoic acid (RA) the mature cells rose to 60 +/- 11.8% compared to 0.7 +/- 1% of the control, while the promyelocytes declined to 8.7 +/- 6.4% (93.3 +/- 5.6% in the control group). Protein kinase C (PKC) activity was significantly increased to 149.3 +/- 156.2 pmol/mg per min compared to 47 +/- 40.9 of the control (p less than 0.01). In HL-60 cells, the activity of PKC increased also from 52.3 +/- 35 to 129.2 +/- 64.6 pmol/mg per min (n = 10, p less than 0.01) after the induction of differentiation with RA. If the leukemia cells were pretreated with a kind of PKC inhibitor such as trifluoperazine, the increase of PKC activity was inhibited, and the rate of nitroblue tetrazolium reduction decreased from 89.9 +/- 7.7% to 62 +/- 25% (n = 6, p less than 0.01) and the mature cells reduced from 63.1 +/- 11.7% to 19.7 +/- 12.2% (p less than 0.01). We presumed that the activity of PKC is closely related to the differentiation of human promyelocytic leukemia cells induced by all-trans-retinoic acid.
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PMID:Studies on the relationship between protein kinase C and differentiation of human promyelocytic leukemia cells induced by retinoic acid. 258 42

cDNA clones complementary to mRNA of cells from patients with chronic lymphocytic leukemia (CLL) were used to examine quantitative changes in the mRNA levels of specific genes in human leukemia leukocytes. Twenty one CLL-positive clones that did not hybridize with placental mRNA were studied. These clones were significantly represented in the mRNA from leukemic leukocytes and were not represent in the mRNA from normal leukocytes. There was high level of expression of 7-2D gene in CLL and B lymphoma cells. RNA hybridizing with clone 7-3G was comparatively highly abundant in CCRF-CEM and EB virus transformed lymphoid cell, while clone 6-1E was highly represented in the mRNAs of Molt 3 and CCRF-CEM cells. The expression of three clones (6-1E, 7-3G and 9-5C) selected from a CLL cDNA library was studied by nucleic acid hybridization in human promyelocytic leukemia cell (HL-60) treated with chemical inducers of cell differentiation. The differentiation of HL-60 cells into macrophage-like cells upon induction by 12-o-tetradecanoylphorbol-13-acetate (TPA) was accompanied by rapid induction of the expression of 6-1E and 7-3G genes. The levels of expression of the 9-5C gene were not altered during macrophage-monocytic or granulocytic differentiation of HL-60 cells. The expression of the 6-1E and/or 7-3G gene was induced by TPA in four of 6 samples derived from patients who achieved complete remission, but not in any of the acute nonlymphocytic leukemia samples from patients who failed to achieve complete remission. These findings suggest that expression of the 6-1E and 7-3G genes is related to macrophage-monocytic differentiation and that alterations of these gene expressions in fresh leukemic cells after one hour of TPA treatment are of prognostic significance in predicting the response to treatment. The primary structure of a cDNA of a gene (6-1E) selectively expressed in CLL was determined. A computer search in the nucleotide sequence data bank did not identify this gene as any other gene. The 677 nucleotide mRNA is composed of a 384 nucleotide pol A tail. Moreover, the sequences of the other cDNA clones (1-6G, 5-2C,5-5G, 6-1G, 7-3G, 7-4A, 8-6G, and 9-5C) are not present in those of the data base of GenBank recorded up to 1988.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Expression of selected genes and oncogenes in differentiated HL-60 cells and primary cells from human leukemias. 258 22

We report the use of the Haemonetics cell processor for monoclonal antibody (MoAb) and complement (C')-mediated lysis of leukemia cells. Using the HL-60 promyelocytic leukemia cell line, we can achieve a six-log depletion of HL-60 colony-forming cells in cell mixtures containing 1% HL-60 cells and 99% normal peripheral blood or bone marrow leukocytes at 10(7)/ml after a single 60-min treatment with an anti-myeloid MoAb, PM-81, plus C'. In this procedure, we continuously infuse a solution of fresh C' while removing medium containing spent C'. We have utilized this procedure to purge remission bone marrow from patients with acute myelogenous leukemia in preparation for autologous bone marrow transplantation. There were no adverse effects to normal progenitor cells of the granulocyte, monocyte and erythrocyte lineages as measured in colony-forming assays. Other potential benefits of using the cell processor method of cytotoxicity include reduction in treatment time and the amounts of costly reagents.
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PMID:Continuous infusion of complement by an automated cell processor enhances cytotoxicity of monoclonal antibody sensitized leukemia cells. 265 17

The classic inhibitor of dihydrofolate reductase (DHFR), methotrexate (MTX), has been shown to be an effective inducer of the differentiation of HL-60 promyelocytic leukemia cells (Bodner A.J. et al.; J. Natl. Cancer Inst. 67:1025-1030; 1981). We have obtained evidence that induction of the differentiation of these cells by MTX, as well as by other folic acid antagonists, is the result of the effects of these agents on purine and thymine nucleotide biosynthesis. Thymidine (10 microM) completely blocked both the cytotoxicity and induction of differentiation produced by the specific inhibitor of thymidylate synthase (TS), N10-propargyl-5,8-dideazafolic acid (CB-3717). Thymidine also blocked the acute cytotoxicity caused by MTX and trimetrexate (TMQ); the induction of differentiation and the loss of proliferative capacity, however, were only partially prevented by thymidine. Hypoxanthine (100 microM), which completely restored antifolate-depleted purine nucleotide levels, had no effect on either the cytotoxicity or the induction of maturation produced by these agents. The growth inhibitory effects and the induction of differentiation caused by dideazatetrahydrofolic acid (DDATHF), which acts on de novo purine nucleotide biosynthesis rather than on DHFR or TS, was completely prevented by hypoxanthine. Hypoxanthine also completely prevented the inhibition of cellular replication and induction of differentiation by MTX and TMQ when combined with thymidine. The findings suggest that the depletion of intracellular thymine nucleotide levels by the antifolates, MTX, TMQ, and CB-3717 is the primary event involved in the maturation of HL-60 leukemia cells produced by these agents and that maturation occurs concomitantly with a high level of cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of the induction of the differentiation of HL-60 leukemia cells by antifolates. 270 Sep 13

Modulation of surface transferrin receptor activity has been associated with leukemia cell differentiation and proliferation. To examine the mechanisms involved in regulating this event, receptor protein and mRNA levels were measured in HL-60 promyelocytic leukemia cells induced to differentiate along the myelocytic and monocytic pathways. Transferrin receptor down-regulation which occurs during granulocytic differentiation by dimethyl sulfoxide, retinoic acid, or aclacinomycin A appears to be kinetically compatible with reduced biosynthesis resulting from reductions in the level of steady-state mRNA. In contrast, genetic modulation does not appear to mediate the initial receptor down-regulation seen during 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation. However, a reduction in levels of receptor message appears to contribute to the maintenance of diminished transferrin receptor activity in these 12-O-tetradecanoylphorbol-13-acetate-treated cells. A common feature of myelocytic and monocytic differentiating cells is the complete inhibition of cellular proliferation observed within 10 to 16 h following a four-fold reduction in surface transferrin receptor. We conclude that the early decline in transferrin receptor levels precludes its regulation as a consequence of the decrease in proliferation, but rather implicates its role in the programmed cessation of growth which is requisite for the terminal differentiation of these cells.
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PMID:Regulation of transferrin receptor in myeloid and monocytic differentiation of HL-60 leukemia cells. 270 40

Tiazofurin is an effective inducer of the maturation of HL-60 promyelocytic leukemia cells, as monitored by increased phagocytic ability and the capacity to reduce nitroblue tetrazolium (NBT). The antimetabolite acts as a potent inhibitor of IMP dehydrogenase, which results in a profound depression in the cellular levels of guanine nucleotides. Flow cytometric analysis of DNA histograms indicated that the commitment of HL-60 cells to differentiate when exposed to tiazofurin was preceded by a transient delay in the G1 phase of the cell cycle. HL-60 leukemia cells enriched in the various phases of the cell cycle by centrifugal elutriation were utilized to further characterize the relationship between the phase of the cell cycle and the commitment to enter a pathway of differentiation. Fractions composed mainly of G1 cells demonstrated an increased capacity to mature when exposed to tiazofurin, whereas fractions containing cells from the S and G2 + M phases of the cell cycle had a lower ability to enter a differentiation pathway. The findings suggest that the commitment of HL-60 cells to mature when exposed to tiazofurin is mediated during the G1 phase of the cell cycle.
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PMID:Induction of the differentiation of synchronized HL-60 leukemia cells by tiazofurin. 271 2

A cDNA that encodes a mouse secretory granule proteoglycan peptide core was isolated from a cDNA library prepared from nontransformed mouse bone marrow-derived mast cells (BMMC) using as a probe a 280-base-pair fragment of a rat cDNA that encodes the proteoglycan peptide core of rat basophilic leukemia (RBL)-1 cells. Based on the consensus nucleotide sequence and deduced amino acid sequence of the cDNA, the mouse BMMC proteoglycan peptide core is 16.7 kDa and contains a 21-amino acid glycosaminoglycan attachment region consisting of alternating serine and glycine residues. When the predicted amino acid sequence of the mouse BMMC proteoglycan peptide core was compared with the predicted amino acid sequences of the homologous molecules expressed in RBL-1 cells and in human promyelocytic leukemia HL-60 cells, the mouse-derived sequence was more closely homologous to the rat sequence than the human sequence except for the length of the serine-glycine repeat region. The N terminus was found to be a highly conserved region of the molecule in the three species, suggesting that this region is important for the structure, function, and/or metabolism of this family of proteoglycans. Nucleotide sequences within the 5' and 3' untranslated regions of the mouse, rat, and human proteoglycan cDNA were conserved. That similar sequences were also present in the corresponding regions of a cDNA that encodes a rat mast cell protease suggests that particular nucleotide sequences may be important for regulation of expression of those proteins that are destined to reside in secretory granules.
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PMID:Molecular cloning of a cDNA that encodes the peptide core of a mouse mast cell secretory granule proteoglycan and comparison with the analogous rat and human cDNA. 272 51


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