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 influence of interferon-alpha 2 (IFN-alpha 2) on the mRNA levels of cellular proto-oncogenes was studied in malignant cells from patients with chronic lymphocytic leukemia (CLL). These cells can be induced to blast transform, differentiate and, in some cases, proliferate upon exposure to IFN. Treatment with IFN-alpha enhanced the levels of c-myc mRNA in malignant cells from the patients, whereas the levels of c-myb mRNA decreased, as measured by slot blot hybridizations. In cells from some patients, an enhanced expression of c-fos and k-ras was observed following exposure to IFN-alpha. No major effect on the expression of c-raf or of enolase was observed in any of the patients following exposure to IFN-alpha, whereas the levels of beta 2-microglobulin mRNA increased. In contrast to the observed effects on oncogene expression in CLL cells, IFN had no major effect on the expression of any of the tested oncogenes in lymphocytes from healthy donors or in B-cells from three neoplastic cell lines (380, FL18, RS). We conclude that IFN-alpha can enhance or repress the expression of several oncogenes in nondividing primary malignant cells from patients with leukemia. We also show that the response of malignant cells from patients to IFN-alpha is different than that seen with neoplastic cell lines which represent a similar stage of B-cell differentiation.
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PMID:Influence of interferon-alpha on the expression of cellular oncogenes in primary chronic lymphocytic leukemia cells. 306 Jul 97

Various agents induce differentiation of human leukemia cells in vitro. Most of these agents cause myeloid differentiation, but phorbol diesters, 1-alpha,25-dihydroxyvitamin D3 (1,25[OH2]D3), and certain lymphokines cause differentiation to monocyte-like cells. The purpose of this study was to determine the cooperative effects of 1,25(OH2)D3 and the lymphokine gamma interferon (IFN-gamma) on HL-60 cell differentiation. The recombinant human IFN-gamma or 1,25(OH2)D3 caused a slight reduction in the proliferation of the HL-60 cells (30%-40% reduction at doses of 100-200 U/ml [0.25-0.50 nM] IFN-gamma, or 5-25 nM 1,25[OH2]D3). HL-60 cells treated with 100 U/ml IFN-G had an eightfold increase in expression of nonspecific esterase (NSE) and a twofold increase in H2O2 production in response to phorbol myristate acetate (PMA). 1,25(OH2)D3 enhanced NSE expression eight- to 30-fold and H2O2 secretion twofold in response to PMA. There was also enhanced expression of HLA-DR and the receptor for C3bi. The 1,25(OH2)D3- and IFN-gamma-differentiating effects appeared to be additive or synergistic. Populations of IFN-gamma-treated HL-60 cells (but not the 1,25[OH2]D3-treated cells) had multinucleated giant cells. The polykaryons had NSE activity and had some properties of macrophage polykaryons or osteoclasts. 1,25(OH2)D3 did not augment the IFN-gamma-induced polykaryon formation.
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PMID:Cooperative effects of gamma interferon and 1-alpha,25-dihydroxyvitamin D3 in inducing differentiation of human promyelocytic leukemia (HL-60) cells. 308 Mar 26

Eighty-five patients with hairy-cell leukemia were treated in a multicentric "open label" study with IFN-alpha 2b and evaluated. Induction therapy was 2 X 10(6) U IFN-alpha 2b/m2, 3 times a week, s.c. The results show this regimen to be highly effective with only a few tolerable and transient side effects consisting mainly of flu-like symptoms. After 6 months of therapy 4% CR, 69% PR, and 16% MR, were noted. In a small group of four patients who had achieved CR or PR, we tested the effect of varying doses for maintenance therapy. Our preliminary results indicate that a relapse caused by interruption of IFN therapy or dose reduction to 3 X 10(6) U given once a week, o.c. could be successfully treated by readministration, or escalating the dosage of IFN. It seems that remission maintenance requires long-term treatment with IFN. In a short-term in vitro test we studied the effect of IFN-alpha 2 on the incorporation of 3H-thymidine and 3H-uridine into hairy cells of five patients. Fort both precursors no appreciable effect was detected. However, after prolonged incubation for 48 h, a significant enhancement of 3H-uridine incorporation was observed, while 3H-thymidine incorporation remained unaffected. Cell marker analysis performed with monoclonal antibodies before and after incubation of hairy cells with IFN-alpha 2 for up to 7 days did not reveal any change of the phenotype of hairy cells.
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PMID:[Recombinant (IFN-alpha 2b) therapy in hairy cell leukemia]. 311 50

Six patients with hairy-cell leukemia were treated with gamma-(IFN-gamma) and alpha-(IFN-alpha-2b) interferon; 3-35 months following splenectomy, treatment was started with 4 X 10(6) U/m2 IFN-gamma sc (iv) every second day for 9-35 weeks. Although the white blood cell counts decreased during therapy from 4.1-49 X 10(9)/l to 1.5-43 X 10(9)/l, no hematological or clinical improvement was obtained. Subsequently (interval 0-13 weeks), IFN-alpha-2b was given at an initial dose of 4 X 10(6) U/m2 sc every second day to all patients. After a treatment period corresponding to that of IFN-gamma administration, a significant hematological improvement was observed in five patients (one early death due to pulmonary embolism). At the last follow-up (9-14 months after start of treatment; maintenance therapy, 1 X 10(6) U every second day), these patients exhibited normal peripheral blood cell counts, and in bone marrow biopsy specimens a marked decrease of hairy cells was seen (1 CR, 3 PR, 1 MR). Adverse reactions including fever, headache, nausea, dryness of the mouth, myalgia, and fatigue did not significantly differ between the two interferon preparations. Whereas IFN-gamma is unlikely to have any significant impact on the course of hairy cell leukemia, IFN-alpha-2b does result in improvement of hematological values and well-being in almost all patients.
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PMID:[Effectiveness of gamma interferon and alpha interferon in hairy cell leukemia]. 311 51

Chronic B-lymphocytic leukemia (B-CLL) cells from 10 patients were cultured serum-free with recombinant interferon (rIFN)-alpha 2, rIFN-gamma, or phorbol ester (TPA) for 5 days. All three agents induced functional differentiation, as evidenced by IgM secretion, without concomitant proliferation. A panel of monoclonal antibodies was used to detect changes in cell surface antigens defining pre-B cells (CALLA), resting B cells (HH1), early (4F2, MHM6) and late (anti-Tac, OKT9) B cell activation, and terminally differentiated B cells (OKT10). The activation markers 4F2, MHM6, and anti-Tac and the plasma cell marker T10 were all significantly induced with TPA, rIFN-alpha 2, an rIFN-gamma, whereas the expression of HH1 decreased. CALLA was detected on substantial proportions of differentiated (4-38%) but not resting (0-4%) B-CLL cells. The CALLA-positive B-CLL cells were negative for nuclear terminal deoxynucleotidyl transferase (TdT). The T9 antigen was expressed on TPA-treated cells (1-16%) only. The present findings indicate novel properties of IFN-alpha and IFN-gamma in inducing terminal differentiation of human monoclonal B cells without prior activation.
Leukemia 1987 Sep
PMID:Effects of recombinant interferon-alpha and -gamma on B-CLL cells in serum-free medium: expression of activation, differentiation, and CALLA antigens. 311 15

In all, 40 major polypeptides ranging in molecular weights from 14.5 to 83 kDa were shown to be induced by IFNs alpha (also by IFN-alpha 2b and beta in a few cases) and gamma in human cultured cells of epithelial (transformed amnion cells (AMA)), fibroblast (proliferating and quiescent MRC-5 fibroblasts), and lymphoid origin (Molt-4). With the exception of a heat shock protein (IEF14 or hs x 70) and two tropomyosins (IEFs 52x and 55), none of these proteins corresponded to polypeptides (proliferation-sensitive or others) previously identified and catalogued by us. IFN-alpha induced the highest number of polypeptides in lymphoid cells, while the response to IFN-gamma was more pronounced in cultured epithelial and fibroblast cells. Several of the polypeptides induced by IFNs alpha and gamma were synthesized (albeit at different rates) by the control untreated cells, and in some cell types such as normal human peripheral blood mononuclear cells many were expressed at high levels. Only IFN-alpha-induced a unique set of proteins (alpha 1, 51 kDa; alpha 2, 15 kDa; alpha 19, 78 kDa; and gamma 10, 83 kDa) in all cultured cell types studied, implying that response to this IFN involves a shared biochemical pathway(s). Both IFN-alpha (also IFN-alpha 2b) and beta induced an identical group of proteins in AMA cells in agreement with the fact that type I IFNs share common receptors. IFNs alpha and gamma induced a few common polypeptides, but only gamma 10 (83 kDa) showed increased synthesis in all cell types exposed to either of these IFNs. A total of 28 major cellular polypeptides were down-regulated by IFNs in the various cell type studied. Different sets of proteins were affected, however, in each system, emphasizing the complexity of the mechanisms underlying the action of these factors. Treatment of synchronized G1 AMA cells with IFNs alpha, beta, or gamma (500 IU/ml, final concentration) did not inhibit their progression from G1 to S-phase as determined by indirect immunofluorescence using PCNA autoantibodies specific for cyclin. These observations were in line with the fact that IFNs did not affect dividin or cyclin(PCNA) synthesis (S-phase specific proteins) at least within the first 17 hr after their addition.
Leukemia 1987 Dec
PMID:Major proteins induced and down-regulated by interferons in human cultured cells: identification of a unique set of proteins induced by interferon-alpha in epithelial, fibroblast, and lymphoid cells. 312 42

THP-1 is an acute monocytic leukemia cell line which acquires phenotypic and functional monocytoid-like features following incubation with mezerein. The current study concerned the modulation of these features by rIFN gamma. rIFN gamma induces the time-dependent enhancement of HLA-DR expression in the presence or absence of mezerein but has no effect on the expression of Leu-M1, Leu-M2, or Leu-M3 antigens. CSF-1 production following mezerein activation was reduced by incubation in the presence of 10(3) and 10(4) units/ml rIFN gamma. This was confirmed through both biological assays with mouse bone marrow cells and an indirect ELISA. In contrast, the concentration of growth inhibitory activity in conditioned medium was increased by rIFN gamma. A small but significant increase in IL-1 beta concentration in conditioned medium was detected using a sensitive double-antibody ELISA and a radioimmunoassay. The results infer that the functional characteristics of this leukemia cell line are modulated by rIFN gamma in a manner qualitatively similar to that reported for IFN gamma treated normal monocytes.
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PMID:Regulation by interferon gamma of function in the acute monocytic leukemia cell line, THP-1. 312 95

Pretreatment of human K562 leukemia cells with rIFN-alpha and rIFN-gamma resulted in decreased susceptibility to lysis by human peripheral blood NK cells. The reduction of NK-susceptibility after IFN treatment was not due to a general effect of IFN on the stability of the cell membrane because the susceptibility of K562 cells to lysis by antibodies plus C, distilled water, or lysolecithin was unaffected. Binding studies with effector cell preparations enriched for NK cells with large granular lymphocyte morphology revealed no difference in binding to control and IFN-gamma-treated target cells. The sensitivity to soluble NK cytotoxic factors was not affected significantly by the IFN treatment. In contrast, the susceptibility of IFN-treated target cells to the cytotoxic activity of purified cytoplasmic granules from a rat large granular lymphocyte tumor was significantly reduced, indicating that the IFN-induced resistance acted at the level of susceptibility to the lytic mechanism of NK cells. However, IFN-alpha was more effective than IFN-gamma in inducing resistance to the cytoplasmic granules although resulting in only a weak resistance in the cell-mediated cytotoxic assay. IFN-gamma but not IFN-alpha caused a reduction in the frequency of effector cells that had reoriented their Golgi apparatus toward their bound target cell. In addition, IFN-gamma treated K562 cells failed to elicit an influx of Ca2+ into effector cells. Taken together, the results suggest that IFN-gamma in addition to an increased resistance to the lytic molecules released by NK cells can also induce changes in the target cells which prevent the triggering and activation of the effector cell.
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PMID:IFN-gamma treatment of K562 cells inhibits natural killer cell triggering and decreases the susceptibility to lysis by cytoplasmic granules from large granular lymphocytes. 313 33

A 93-kDa tyrosine protein kinase (p93) identified previously as the gene product of the c-fes proto-oncogene, is highly expressed in HL-60 leukemia cells induced to differentiate to the granulocyte or monocyte phenotype. We have now studied the relationship of p93 to the differentiation process by using a dimethyl sulfoxide (DMSO)-resistant subline of HL-60 cells (HL-60/DMSO) or the parental cell line treated with peptide or protein substrates of p93. Treatment of HL-60/DMSO cells with DMSO induced neither differentiation nor the expression of p93; however, cotreatment with IFN-alpha and DMSO resulted in partial differentiation and the concomitant induction of p93 activity. Treatment of wild-type HL-60 cells by the coaddition of the p93 substrates poly(Glu,Tyr)1:1, poly(Glu,Tyr)4:1, poly(Glu,Ala,Tyr)6:3:1, angiotensin II or vasoactive intestinal peptide with DMSO or IFN-tau partially blocked differentiation and concurrently diminished the induction of p93 activity. The inhibitory concentrations of the p93 substrates were related to their Km values. These results indicate that there is an obligatory association between the expression of p93 and granulocyte/monocyte differentiation in this cell line.
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PMID:Association of p93c-fes tyrosine protein kinase with granulocytic/monocytic differentiation and resistance to differentiating agents in HL-60 leukemia cells. 316 57

We have identified a leukemia-differentiating activity (LDA) in medium conditioned by the LD-1 melanoma, a G-CSF secreting human tumor line. Partially-purified LDA induces HL-60 cells to produce superoxide, become phagocytic, and to develop macrophage-like morphology and surface markers. The LDA markedly suppresses clonal growth in agar of HL-60 cells, and cells of the human myeloid leukemia lines PBL 985 and K562, but does not suppress clonal growth of the B-lymphoblast lines Raji and Daudi. The molecular weight of this material is approx. 40,000 daltons. It can be separated from the bulk of the colony stimulating activity on phenyl sepharose chromatography. The LDA is not neutralized by antibodies to G-CSF, GM-CSF, IFN alpha, IFN gamma, TNF, urokinase, and tissue plasminogen activator, and is not inhibited by preincubation with aprotinin. The LDA in conditioned medium may be different from previously described differentiating factors, and may represent an additional class of human growth regulators.
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PMID:Leukemia-differentiating activity expressed by the human melanoma cell line LD-1. 316 98


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