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)

We have previously shown that non-cytotoxic concentrations (600-1200 U/ml) of recombinant mouse tumour necrosis factor-alpha (TNF-alpha) can induce differentiation of a subclone (JCS) of the WEHI-3B myelomonocytic leukaemia cell line into mature cells with the characteristics of macrophages. In the present study, the effects of recombinant mouse interleukin-4 (IL-4), either alone or in combination with mouse TNF-alpha, on the growth and differentiation of JCS cells were examined. IL-4 alone (20-5000 U/ml) inhibited the growth of JCS cells in a dose-dependent manner but did not induce cell differentiation. However, combinations of IL-4 and TNF-alpha acted in synergy to inhibit cell proliferation and induce monocytic differentiation of JCS cells, as shown by increased expression of the macrophage differentiation antigens (F4/80, Mac-1), stimulation of phagocytic activity, induction of non-specific esterase and NBT-reducing activities, increased plastic adherence and morphological criteria. Similar synergistic interactions were also shown by human TNF-alpha and mouse IL-4, indicating that TNF-alpha might exert its effects through the low-affinity (p55) TNF receptors. Moreover, the clonogenicity of JCS cells in vitro and their tumorigenicity in vivo were significantly reduced by combined TNF-alpha and IL-4 treatment. Our results indicate that TNF-alpha can act as a differential signal for JCS cells and that its effects are modulated by IL-4. Therefore, the combination of TNF-alpha and IL-4 may be useful in the treatment of some forms of myelomonocytic leukaemia.
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PMID:Synergistic effect of IL-4 and TNF-alpha in the induction of monocytic differentiation of a mouse myeloid leukaemic cell line (WEHI-3B JCS). 813 22

All-trans retinoic acid (ATRA) is a potent inducer of differentiation and cell death in malignant cells. Its effect is known to be mediated through binding to specific nuclear (RARs and RXRs) or cytoplasmic (CRABP) proteins. ATRA is strikingly effective in acute promyelocytic leukemia (the AML3 subtype) inducing a high incidence of complete remissions. Paradoxically, most AML3 cells harbor an abnormal retinoic acid receptor (PML/RAR alpha) resulting from the t(15;17) translocation. Though few AML3 patients do not respond to ATRA therapy, individualization of these cases is of practical importance. Recently the RAR alpha gene has been demonstrated to be involved in a novel fusion transcript (PLZF/RAR alpha) through a t(11;17) translocation. We describe here the second case of such a patient with a t(11;17)-PLZF/RAR alpha leukemic clone. Southern analysis revealed that the breakpoint in the RAR alpha gene was within the second intron (as for PML/RAR alpha) and the intron separating the second and third zinc finger of the PLZF gene. In vitro, the leukemic cells did not show increased NBT reduction or loss of self-renewal after incubation with ATRA. After therapy with ATRA, only partial remission was obtained. These results suggest that the t(11;17) (PLZF/RAR alpha) case of this study was less responsive to ATRA therapy than t(15;17) (PML/RAR alpha) cases and raises the question of the definition of this novel AML subtype.
Leukemia 1994 Feb
PMID:Poor response to all-trans retinoic acid therapy in a t(11;17) PLZF/RAR alpha patient. 830 56

We have screened more than one thousand synthetic and natural chemicals to explore differentiation inducers and found that daidzein has potent differentiation-inducing activity for human leukemia HL-60 cells, both in vitro and in vivo. In vitro study showed that daidzein at concentrations exceeding 10 micrograms/ml caused inhibition of HL-60 cells; and it induced differentiation of the cells into granulocytic lineage as judged by NBT reduction activity, phagocytic ability and morphological characteristics. Flow cytometry study indicated that daidzein arrested HL-60 cells in the G1 phase. The growth of HL-60 cells in the subrenal capsules of mice and in diffusion chambers implanted into the peritoneal cavities of mice was inhibited by 50 mg/kg daidzein. HL-60 cells treated with daidzein in vivo also exhibited characteristic morphological changes of matured cells. Moreover, the colony forming efficiency of HL-60 cells in diffusion chambers in mice was markedly inhibited by the administration of daidzein.
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PMID:Differentiation of promyelocytic leukemia cells HL-60 induced by daidzein in vitro and in vivo. 835 24

The individual roles of two types of TNF receptors (55 kDa and 75 kDa) in induction of differentiation of human myeloblastic leukemia ML-1 cells were investigated using three monoclonal antibodies. The antibody htr-9, which recognizes the 55 kDa receptor, induced differentiation of ML-1 cells. Utr-1, which recognizes the 75 kDa receptor, blocked 125I-TNF binding by about 80% and inhibited by about 80% the TNF-induced NBT reducing activity. Htr-5 recognizes the 55 kDa receptor, blocked 125I-TNF binding by about 20% and inhibited by about 60% the TNF-induced NBT reducing activity. The data suggest that either of the two TNF receptors alone can mediate signals for the differentiation of ML-1 cells, and that simultaneous stimulation of both receptors will induce differentiation more effectively.
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PMID:Roles of two tumor necrosis factor receptors in induction of differentiation of ML-1 cells. 839 78

Low concentrations of geranylgeranylacetone (GGA), known as an antiulcer agent (Teprenone), induces differentiation of various human myeloid leukemia cell lines. The cell lines examined in the present study were myeloblastic ML1, histiocytic U937, promyelocytic HL60, and multipotential K562. All of these cell lines were induced to differentiate by 20 microM GGA, as measured by NBT staining. Neither polyprenylacetones, with more or fewer isoprene units than the geranylgeranyl group, nor polyprenylalcohols had no differentiation-inducing activity. GGA used in combination with RA or TNF-alpha increased ML1 cell differentiation. The present results suggest that GGA may be a useful agent in differentiation therapy of leukemia.
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PMID:Geranylgeranylacetone used as an antiulcer agent is a potent inducer of differentiation of various human myeloid leukemia cell lines. 846 27

Macrophages and their products may exert either inhibitory or stimulatory effects on malignant cells,thus preventing or supporting tumor growth, however, the mechanisms of this interaction are not fully understood. It was the aim of the present study to elucidate the role of macrophage activation during the growth and rejection of highly immunogenic murine leukemia P388/adria cell line which was made resistant by suboptimal treatment of mice with adriablastin during the serial passaging of parental P388 cells. The functional activity of peritoneal macrophages and the serum level of cytokines IL-1 beta, IL-6 and TNF-alpha were studied in different groups of mice. Mice from group 1 (control) received saline. Mice from group 2 (tumor bearers) with fast subcutaneous (s.c) 100% tumor growth were compared with animals from group 3 that had been twice previously immunized with lethally irradiated P388/adria cells and later inoculated with viable tumor cells. Tumors grew in only 25% of group 3 animals with a significant delay. The activity of peritoneal macrophages was studied by NO2- production and the NBT-test. Both tests revealed the early high systemic activation of macrophages in group 2. This coincided with the elevation of serum TNF-alpha and IL-6 levels. This effect was not dependent on whether alive or lethally irradiated tumor cells were inoculated. The NO2- production by peritoneal macrophages correlated well with the dynamics of serum cytokine levels while the NBT-test did not. Studies on group 3 showed total abrogation of early macrophage and cytokine reactions. The production of inhibitory factors by macrophages in previously immunized mice is suggested. The fact that the early activation of macrophages and increase of serum levels of proinflammatory cytokines occurred in animals with fast growing tumors, which was decreased or absent in animals with tumor delay or rejections, allows us to suppose that this reaction plays more a supporting than a protecting role for tumor growth.
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PMID:Involvement of macrophages and cytokines into rejection mechanism of the drug-resistant and immunogenic murine lymphoma P388/adria. 871 29

All-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). Nevertheless, most of these patients develop RA resistance and relapse. The mechanisms of RA resistance by APL cells are still unclear. To understand the characteristics of human leukemia, human leukemic cell lines are useful tools for study. APL cells have a strikingly low proliferation potential in vitro; thus, only one APL cell line has been established. We developed a novel APL cell line (UF-1) from a patient clinically resistant to all-trans RA. Cell surface markers in the UF-1 cells were positive for CD7, CD13, CD33, and CD38. Cytogenetic analyses revealed additional abnormalities, 46XX, add(1)(q44), add(6)(q12), add(7)(q36), t(15;17) (q21;q21). Molecular analyses showed a PML/RAR alpha fusion transcript. Sequence analysis of the RAR alpha gene in RA-resistant HL-60 cells disclosed a point mutation in codon 411 (C to T substitution), whereas UF-1 cells showed the normal sequence. All-trans RA did not change morphological features of the cell, NBT reduction activity, or their expression of CD11b antigens as determined by FACS analysis except at 10(-6) mol/L. RA also did not alter the growth curve of the cells as determined by the MTT assay. These findings suggest that the UF-1 cell is the first permanent cell line with spontaneous RA-resistant APL cells. This RA-resistant APL cell line may be a useful model for molecular studies on the block of leukemic cell differentiation and as a means to investigate the mechanisms of RA resistance.
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PMID:Establishment and characterization of a novel acute promyelocytic leukemia cell line (UF-1) with retinoic acid-resistant features. 878 40

Since arsenic compounds reportedly induced complete remission in patients with acute promyelocytic leukemia (APL) in China, we studied the in vitro effect of metal ions including As3+, As5+, Cd2+, Ga3+, Ge4+, Hg2+, Se4+, and Zn2+ on myeloid cell lines. One-tenth microM As3+ caused growth suppression and morphological changes resembling differentiation in NB4 cells, but did not induce the maturation-markers, CD11b, CD14 and NBT-reductase. More than 1 microM As3+ caused the time- and dose-dependent apoptosis of NB4 cells. Other metal ions at the same concentrations induced neither morphological changes nor apoptosis in myeloid cell lines including NB4, whereas Cd2+, Ga3+, and Hg2+ induced moderate and non-specific growth suppression. All-trans retinoic acid (ATRA)-resistant NB4 cells were similarly sensitive to As3+. Among the clinical leukemia samples, As3+ was selectively toxic to APL cells regardless of ATRA-sensitivity. These findings suggest that APL cells are sensitive to As3+, and that As3+ acts on APL cells via a different pathway than ATRA.
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PMID:Toxic effects of arsenic (As3+) and other metal ions on acute promyelocytic leukemia cells. 907 24

The human promyelocytic leukaemia cell line, HL-60, was investigated with regard to proliferation and terminal differentiation following irradiation. The cells were X-irradiated and induced with 1.25% dimethyl sulfoxide (DMSO) towards the granulocytic lineage. Proliferation was measured via cell growth, clonogenicity and the bromodeoxyuridine/DNA incorporation assay. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA) expression was used to discriminate cycling from non-cycling cells. The differentiation obtained was proved by testing for the immune function of the respiratory burst (NBT reduction test). The HL-60 cells studied revealed a high radiosensitivity (D0 = 0.63 Gy). After induction with DMSO, declines in cell growth, clonogenicity and PCNA positivity of the cells indicated a decrease in proliferation and an increase in differentiation. Starting on day 2 in culture, irradiation after seeding with 1 Gy accelerated the loss of the PCNA expression in induced cells (46% v. 3% PCNA-negative control cells on day 3). Induced cells gained the capability of exerting the respiratory burst, which was found to be dose-dependent radiosensitive (42%, and 12% NBT-positive cells after 1 and 2 Gy, respectively, v. 53% NBT-positive control cells on day 8). Subpopulations in the cell line were evident in all parameters investigated. We discuss the HL-60 cell, not only as a model comparable to human progenitor cells, but also as a suitable tool in radiobiological research with regard to proliferation and differentiation following ionizing irradiation.
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PMID:Proliferation kinetics and PCNA expression of HL-60 cells following ionizing irradiation and granulocytic differentiation. 911 20

All-trans retinoic acid (ATRA) induces differentiation of acute promyelocytic leukemic (APL) blasts from patients with t(15;17) APL. However, blasts from patients with the t(11;17) variant do not differentiate in response to ATRA. Our group has identified a variant of APL characterized by t(5;17) and expression of the NPM-RAR fusion gene product. From case reports it has been difficult to establish whether ATRA induces clinical responses in patients with this variant. In order to determine whether t(5;17) blasts differentiate with ATRA, we harvested mononuclear bone marrow cells from a patient with t(5;17) APL at time of relapse and cultured them in medium containing ATRA. Morphologic analysis of cytospins after 7 days of culture revealed that 60% of cells in the ATRA-treated culture had differentiated into mature neutrophilic forms, as opposed to less than 1% in the control culture. Seventy-three percent of cells acquired NBT positivity after exposure to ATRA, compared with 1% in the control culture. These results indicate that t(5;17) blasts retain the ability to terminally differentiate in response to retinoic acid.
Leukemia 1997 Jul
PMID:Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. 920 84


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