Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among 52 patients diagnosed as acute myeloid leukemia (AML), nine cases were found in which interleukin-5 (IL-5) induced a proliferative response in the leukemic cells, as measured by the stimulation of DNA synthesis or colony formation in vitro. All cases (n = 7) with the cytogenetic abnormality t(8;21)(q22;q22) belonged to this group of IL-5 responders. Of the additional two cases, one had an apparently normal karyotype, but the other expressed a dicentric chromosome 21, an abnormality also involving the breakpoint region 21q22. The leukemic cells of the IL-5 responsive patients could also be stimulated to proliferate by IL-3, GM-CSF and G-CSF, and in some cases by IL-6 or M-CSF. Immunophenotypic analysis revealed the presence of the immature hematopoietic cell antigen CD34, the myelomonocytic maturation antigens CD13 and CD33, in association with the B-cell related surface marker CD19 on the leukemic cells. Immunoglobulin mu and T-cell receptor beta-genes in the leukemic cells were in germline configuration. Upon incubation in colony culture, clonogenic cells were capable of producing progeny showing eosinophilic or neutrophilic maturation following stimulation with IL-5 or G-CSF, respectively. It is concluded that IL-5 responsive AML represents a subgroup of leukemia with distinct immunotypic and cytogenetic features.
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PMID:Acute myeloid leukemias with chromosomal abnormalities involving the 21q22 region identified by their in vitro responsiveness to interleukin-5. 171 59

The blast cells of acute myeloblastic leukemia (AML) usually require growth factors for optimum proliferation in cell culture. Growth factors also affect the sensitivity of AML blast cells to cytosine arabinoside (ara-C). Others have reported that factor-treated cells are more ara-C sensitive than blasts in culture without factors. These authors have reported previously that AML blasts grown with rG-CSF, with or without GM-CSF, are more sensitive than cells in GM-CSF alone. This paper reports experiments which show that changes in the ara-C sensitivities of blast cells in different growth factors are not explained by changes in the percentage of cells in the DNA synthesis (S) phase of the cycle. Blasts freshly obtained from five AML patients were cultured in either rG-CSF, rGM-CSF, or rIL-3; they were then exposed to 20 min pulses of either high specific activity tritiated thymidine (3HTdR) or a high concentration of ara-C. Regardless of the factor present, the pulse of 3HTdR decreased the number of clonogenic cells by about 50%, the result expected for actively proliferating cells with an S phase occupying about half the cycle time. The same result was found for four of the five blast cell populations grown in G-CSF and pulsed with ara-C; in contrast, clonogenic cells grown in GM-CSF or IL-3 from these four populations were not killed by ara-C. The blasts from the fifth patient were ara-C resistant under all conditions. It was concluded that exposure to GM-CSF or IL-3 decreased ara-C sensitivity in blasts that were actively making DNA. The observation was explored in more detail using a cell line (OCI/AML-1a) that is both ara-C sensitive and growth factor dependent. These studies showed that about 15 h of growth in factor are required for a change in ara-C sensitivity.
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PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 protect leukemic blast cells from ara-C toxicity. 171 8

The hemolymphopoietic growth factors, including the colony-stimulating factors (CSF) and interleukins (IL), are described and categorized on the basis of their biological features in laboratory systems. Although these agents are varied and exceptions exist, in general they lack lineage specificity although they may express lineage-predominant activity. They act at multiple levels of hemolymphopoietic cell differentiation, demonstrate additive or synergistic effects when combined in vitro, require surface receptors on target cells to directly express their activity, and may be produced by a variety of cells. This framework of behavioral generalizations, completed by the specifics of each factor's activity, despite the artifactual and simplified nature of in vivo systems, forms the basis for concepts of in vitro activity and for clinical applications. Hemolymphopoietic growth factors studied in the clinic have demonstrated impressive and important activity, validating much of the in vitro data. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have clearly reduced neutropenia and infection rates when administered following conventional chemotherapy and high-dose chemotherapy followed by autologous bone marrow transplantation. To a varying degree, similar results with G-CSF and/or GM-CSF have been described in other diseases including acute myelogenous leukemia (AML) treated following induction chemotherapy, myelodysplastic syndrome, hairy cell leukemia, aplastic anemia, and chronic neutropenias. In preliminary studies IL-3 has been shown to have similar qualitative activities. However, these agents have not demonstrated a reproducible salutary impact on platelet or red cell lineages. Adverse effects on platelet counts and/or platelet recovery have been noted. Additionally, hemolymphopoietic growth factor receptors have been identified on malignant cells, suggesting that these factors could stimulate neoplastic growth. Studies with GM-CSF and IL-3 have demonstrated blast proliferation in some cases of AML and myelodysplasia, underscoring the capacity of these agents to stimulate the growth of myeloid leukemia. No clinically evident impact of these factors upon the growth of solid tumors has been identified but this issue has not been adequately studied. The toxicity of these agents has been surprisingly limited and appears to be related to their biologic activities. Hemolymphopoietic growth factors as single agents have broad clinical applications in cytopenias. Several methods for enhancing the clinical activity of these agents are under study, including the use of combinations of growth factors synergistic in vitro.
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PMID:Recombinant human hematopoietic growth factors in the treatment of cytopenias. 172 85

We have examined the effect of recombinant interleukin 3 (rIL-3) on the metabolism of high-dose cytosine arabinoside (Ara-C), an S-phase-specific agent, in normal human bone marrow mononuclear cells (BMMC) and leukemic blasts from patients with acute myeloid leukemia (AML). Exposure to rIL-3 for 24 h significantly increased the percentage of cycling S-phase cells in normal BMMC as well as leukemic cells. A concomitant expansion of intracellular deoxycytidine triphosphate (dCTP) levels occurred to a significantly greater extent in normal BMMC. Compared to treatment with Ara-C (10 mumol/liter) alone, prior and coadministration of rIL-3 with Ara-C increased Ara-CTP levels in leukemic blasts. However, an identical treatment produced significantly higher dCTP levels in normal BMMC, resulting in a significantly lower mean Ara-CTP to dCTP pool ratio in normal BMMC compared to that observed in each of the samples of AML blasts. Following treatment with Ara-C plus rIL-3 versus Ara-C alone, the alteration in Ara-C DNA incorporation corresponded with the change in Ara-CTP to dCTP ratio observed in normal BMMC and AML blasts. The differential effect of rIL-3 on the metabolism of high-dose Ara-C in normal versus leukemic cells may indicate a role for rIL-3 in enhancing the selectivity of Ara-C toward leukemic myeloblasts.
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PMID:Differential effect of interleukin 3 on the metabolism of high-dose cytosine arabinoside in normal versus leukemic human bone marrow cells. 189 53

The responses to retinoic acid (RA) of acute myeloblastic leukemia (AML) blasts and normal hemopoietic progenitors was examined under defined growth factor conditions. For the leukemic cells marked patient to patient variation was seen; blast colony formation by cells from some patients was stimulated by RA without growth factors or in the presence of recombinant granulocyte colony-simulating factor (rG-CSF), recombinant granulocyte-macrophage-CSF rGM-CSF and recombinant interleukin-3 (rIL-3); for other populations inhibition was observed under the same conditions. Some blast cells were stimulated by RA in the presence of rGM-CSF and rIL-3 and inhibited when cultured with RA and rG-CSF. Supernatants prepared from blasts cultured with RA and growth factors did not show activities that were not readily explained by the carry-over of growth factors; this result did not provide evidence that RA and growth factors interact to produce factors. Titrations of RA showed that activity was first observed at concentrations of 10(-9) M and was maximum at concentrations of 10(-7) M. Different effects of RA in combination with rG-CSF compared with rGM-CSF or IL-3 were not seen when the cells were tested in suspension culture rather than in methylcellulose, a finding that may be interpreted to mean that the interaction between RA and factors affects terminally-dividing blast cells. Three normal bone marrow samples were cultured with RA and growth factors. Colony formation was stimulated by RA in the presence of rGM-CSF or rIL-3 but inhibited by RA with rG-CSF. Thus a differential effect of RA in combination with growth factors occurs in normal hemopoietic cells and persists in some AML populations.
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PMID:Interactions between retinoic acid and colony-stimulating factors affecting the blast cells of acute myeloblastic leukemia. 196 Oct 35

We report the results of a preclinical study comparing four different purging protocols using a promyelocytic human cell line HL-60 and myeloid leukemic progenitor cells (colony-forming unit-leukemic [CFU-L]) from acute myelogenous leukemia (AML) patients assayed in semisolid culture. We studied the antileukemic effect of (1) Single-cycle complement-mediated lysis by two different monoclonal antibodies (MoAbs) (M195 [CD33] and F23 [CD13] 40 micrograms/mL), reactive with distinct antigens found on early myeloid cells and monocytes, used alone and in combinations; (2) 4-Hydroperoxycyclophosphamide (4-HC) (80 mumol/L or 100 mumol/L) alone; or (3) combined with VP-16 (5 micrograms/mL) and (4) a cocktail of 1 through 3 as above (combined immunochemotherapy). More than 4 logs of HL-60 tumor cell elimination were observed after 1 hour of incubation with both MoAbs plus 4-HC + VP-16 while the single treatment (immunotherapy or chemotherapy) provided 1.5 and 3.5 logs of colony-forming inhibition, respectively. When the same protocols were tested on cryopreserved leukemic cells from eight patients with AML, we observed a mean value of CFU-L inhibition of 92.3% +/- 2.5% SD, 95.5% +/- 1.4% SD, and 99% +/- 0.8% SD after MoAbs and complement lysis, 4-HC, and 4-HC + VP-16 treatment, respectively. The combined treatment of MoAbs and 4-HC + VP-16 produced more than 3-log reduction of CFU-L colony formation. By comparison, the mean recovery of committed normal bone marrow progenitors after incubation with MoAbs and complement was 12% for CFU-granulocyte-macrophage (CFU-GM), 22.9% for burst-forming unit erythroid (BFU-E), and the recovery following 4-HC + VP-16 treatment was 4.4% for CFU-GM and 5.6% BFU-E. In subsequent experiments, highly purified CD34+ blast cells, enriched by positive selection, and stimulated in liquid culture by cytokines (interleukin-1 [IL-1], IL-3, and combination of both) or MO-conditioned medium (MoCM), demonstrated that immunochemotherapy spares hematopoietic colony-forming cells earlier than day 14 CFU-GM, in vitro.
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PMID:Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination. 201 6

We investigated the induction of tissue factor by lymphokines in human monoblastic leukemia cell lines (U937) and leukemic cells from AML (acute myelogenous leukemia) patients. After incubation for 24 h, IL-2 enhanced the intracellular tissue factor 15-fold with U937 cells, and GM-CSF enhanced it 6-fold. In contrast, other lymphokines, such as IL-1-alpha, IL-1-beta, IL-3, IL-4 and G-CSF, did not affect the activity of tissue factor. The leukemic blasts, depleted of T-lymphocytes, taken from five out of 16 AML patients showed a 2.5-14-fold increase in the activity of tissue factor per cell following incubation with 200 u/ml of IL-2 for 72 h. The IL-2 induced tissue factor activity more markedly than GM-CSF. Tissue factor stimulation by IL-2 did not correlate with the expression of the IL-2 receptor, Tac, but correlated well with FAB classification of AML cells. IL-2 responders were found in M4 and M5 subtypes only, but not all M4/M5 leukemias responded to IL-2. These findings indicate that IL-2 can mediate the tissue factor induction in the monocytic type of AML and the effect is not mediated by Tac receptors. This may shed a new light on our understanding of hypercoagulability in acute monoblastic leukemia.
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PMID:Induction of tissue factor by interleukin-2 in acute myelogenous leukemia (AML) cells. 208 39

We recently described an IL-1 inhibitor found in urine of febrile patients. It is a 26-kDa glycoprotein that acts by blocking the binding of IL-1 to its receptor. In a search for a cell source for the urinary IL-1 inhibitor, we tested three promyelocytic cell lines, H-161, AML-193, and HL-60, for their ability to produce this protein. Under normal culture conditions none of these cell lines produce detectable IL-1 inhibitory activity. The H-161 cells were treated with differentiation-inducing agents, i.e., sodium butyrate, hemin, retinoic acid, DMSO, vitamin D3, and PMA alone or in combination with IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, TNF-alpha, IFN-gamma, granulocyte-CSF, macrophage-CSF, granulocyte/macrophage-CSF (GM-CSF), and Con A and tested for the production of IL-1 inhibitor. Production of IL-1 inhibitor was detected in cell supernatant, when H-161 cells were differentiated to adherent macrophage-like cells under the influence of PMA followed by a second signal provided by GM-CSF. Treatment of the other two cell lines, AML-193 and HL-60, with PMA plus GM-CSF also yielded similar IL-1 inhibitor protein. Partial purified H-161-derived IL-1 inhibitor showed specific binding to IL-1R-bearing cells and blocked the binding of IL-1 to its receptor and is thus similar to the urinary-derived molecule. We conclude the GM-CSF provides a signal to adherent macrophage-like cells to become "inhibitory macrophages" and to produce a competitive inhibitor of IL-1.
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PMID:Human granulocyte-macrophage colony-stimulating factor plus phorbol myristate acetate stimulate a promyelocytic cell line to produce an IL-1 inhibitor. 214 81

Treatment of the AML-193 leukemic cell line with phorbol myristate acetate (PMA) resulted in the loss of their ability to proliferate in response to GM-CSF or IL-3. This was not due to a change in number or affinity of GM-CSF receptors, but possibly resulted from an other cellular mechanism. The AML-193 differentiated cells acquired the ability to phagocytose glutaraldehyde-fixed E.coli in a similar fashion to mature macrophages. In addition the PMA-differentiated AML-193 cells now secreted a factor which specifically inhibited the binding of interleukin-1 (IL-1) to its receptor on the murine thymoma cell line EL-4.6.1C10. The synthesis of this inhibitor was further increased by the addition of GM-CSF or IL-3. Pulse labelling experiments showed that this activity was due to a 26 kDa protein that bound to the IL-1 receptor even in the presence of neutralizing antibodies against IL-1 alpha or IL-1 beta, and this binding was only antagonized by IL-1 alpha or IL-1 beta. In contrast, peripheral monocytes obtained from the blood of normal donors, when induced with either GM-CSF or IL-3, produced large quantities of inhibitor in the absence of PMA. This report clearly shows that a leukaemic cell line can respond to GM-CSF and IL-3 in different ways before and after in vitro differentiation.
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PMID:Granulocyte-macrophage colony stimulating factor and interleukin-3 regulate the production of an interleukin-1 inhibitor by the differentiated AML-193 leukemic cell line. 215 93

The mechanisms that are involved in the control of the normal differentiation of hematopoietic progenitor cells are largely unknown. Moreover, little is known concerning the types of genes that can alter the ability of hematopoietic progenitors to differentiate and cause transformation. One approach to the latter has been to use retroviral induced IL-3-dependent myeloid leukemia cell lines to identify transforming genes by their activation through insertional mutagenesis. This approach has implicated alterations in c-myb in transformation and has identified a novel transcriptional factor of the zinc finger family that is frequently activated in murine myeloid leukemias and in some cases of human AML. Using this approach it should be possible to identify additional myeloid transforming genes. The identification and characterization of the genes will provide important information and approaches to the study of the regulation of differentiation in normal hematopoiesis.
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PMID:Insertional mutagenesis and transformation of hematopoietic stem cells. 216 32


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