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)

The in vitro growth response of bone marrow and blood cells to granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) was studied in 18 acute myeloid leukemia (AML) patients using semisolid and suspension cultures. In 80% of the cases growth of leukemic progenitor cells was stimulated by GM-CSF and/or G-CSF, as judged by colony or cluster formation. In acute promyelocytic leukemia [t(15;17)], G-CSF stimulated and maintained the leukemic progenitors only transiently but fully stimulated the residual normal granulocyte/macrophage colony-forming units (CFU-GM). In some cases of M2 and M4 leukemia, G-CSF enhanced markedly the production of mature but cytochemically abnormal neutrophils. In some cases of M1 leukemia, neither CSF stimulated leukemic progenitors but instead stimulated only residual normal granulopoiesis. Spontaneous colony formation was observed in 20% of cases and was correlated with high-grade leukemic growth in vivo and a poor response to chemotherapy. The differing effects of the CSFs upon leukemic cells and residual normal granulopoiesis may have some implications for the clinical use of GM-CSF and G-CSF to overcome infectious complications.
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PMID:In vitro growth response to G-CSF and GM-CSF by bone marrow cells of patients with acute myeloid leukemia. 169 Aug 27

Acute mixed lineage leukemias (MLL) are a heterogeneous group of acute leukemias that express morphologic and/or immunophenotypic features of more than one hematopoietic cell line. The ontogenetic significance of this mixed lineage expression is unclear. We therefore studied the conviction of the lineage commitment in a group of MLL by examining the in-vitro response of five CD2+ (E-rosette receptor) acute myelogenous leukemia (AML) to a panel of proliferation and differentiation-inducing agents. Three of the five CD2+ AML were TdT-positive. Antigen receptor gene studies revealed no rearrangements at either the T beta or immunoglobulin heavy chain gene loci in any case. When blast-enriched cell populations were placed in short term suspension cultures with PHA, IL-2, PHA + IL-2, GM-CSF or TPA, three of the leukemias responded in a similar fashion while the remaining two cases showed no response. In the three MLL that responded to the in-vitro culture manipulations, features indicative of differentiation along the monocytic lineage pathway were observed. This differentiation was not pronounced in the presence of the phorbol ester TPA, and was manifested by loss of CD2 and CD7 expression, continued expression of myeloid antigens, and the development by the blasts of morphologic and cytochemical characteristics of monocytic cells. None of the five MLL showed any evidence of induced maturation along the T-lymphocyte line of differentiation with any of the agents used. rGM-CSF was the only exogenously added agent to induce proliferation; the proliferative response was slight and was seen in only one of the five leukemias. Therefore, the phenotypic expression of CD2 and CD7 in blasts from MLL is not indicative of irreversible commitment to T-lymphocyte development. The in-vitro loss of T-cell antigens in concert with the development of monocytic features in three of the five CD2+ AML in this study suggests the leukemic cells were preferentially committed to a non-lymphoid lineage differentiation pathway.
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PMID:The in-vitro response of CD2-positive acute myelogenous leukemia to proliferation and differentiation inducing agents. 169 68

The cytokine interleukin-1 (IL-1) plays a role in the regulation of normal as well as leukemic hematopoiesis. In acute myeloid leukemia (AML), IL-1 induces autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) production, and these factors may then synergistically induce proliferation in AML blast cells. In this report, we show that IL-1 stimulates DNA synthesis of highly enriched normal bone marrow blast cells (CD34 positive, adherent cell depleted, CD3/CD14/CD15 negative). The stimulative effect of IL-1 can be blocked with neutralizing anti-TNF alpha and anti-GM-CSF antibodies and, most efficiently, by the combination of anti-TNF alpha and anti-GM-CSF, but not with anti-G-CSF antibody, suggesting that IL-1-induced proliferation was initiated through TNF and GM-CSF release. Concentrations of TNF and GM-CSF increased in the culture medium of normal bone marrow blast cells after IL-1 induction. Of the IL-1-induced cells, 12% were positive for GM-CSF mRNA by in situ hybridization, as opposed to 6% of non-induced cells. Thus, in addition to its effect on leukemic blast cells, IL-1 also acts on normal marrow blast cells. We propose a scheme where IL-1 stimulation of normal bone marrow blast cells leads to the induction of TNF alpha and GM-CSF, which in association stimulate DNA synthesis efficiently according to a paracrine or autocrine mechanism within the marrow blast cell compartment.
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PMID:Interleukin-1 alpha also induces granulocyte-macrophage colony-stimulating factor in immature normal bone marrow cells. 169 8

By a colorimetric assay with dye (neutral red), the effects of recombinant human hemopoietic growth factors (rhG-CSF, rhGM-CSF, rhIL-3 and rhEPO) on the proliferation of leukemic blasts in vitro were investigated. Leukemic blasts were obtained from eight patients with acute myeloid leukemia (AML) (M1: two cases, M3: two cases, M4: four cases) and from four patients with acute lymphoid leukemia (ALL) (L2: four cases). It was shown that rhG-CSF, rhGM-CSF and rhIL-3 stimulated the blast proliferation in most cases of AML, although the degree and pattern of responses showed a striking variability in different patients. Moreover, rhGM-CSF and rhIL-3 also stimulated the leukemic blasts from some cases of ALL. No clear morphological modification providing evidence for terminal differentiation was observed when assessed by Wright stain. On the other hand, rhEPO did not have any stimulating effects on leukemic blasts in all cases. These results indicate the necessity of investigating the responses of leukemic blasts to hemopoietic growth factors in each patient prior to clinical use of such factors. For this assay, neutral red uptake method is useful because of its simplicity, rapidity, precision and convenience for handling a large volume of materials.
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PMID:Usefulness of neutral red uptake method for investigation of the effects of recombinant hemopoietic growth factors on leukemic blasts proliferation. 169 1

A strictly factor-dependent cell line (UCSD/AML1) was established from a patient with the syndrome of multilineage acute leukemia with high platelets. The patient's cells and the cell line karyotype were 45,XX,-7,t(3;3)(q21;q26), typical of the syndrome of acute leukemia with high platelets. The cell line expresses CD34, CD7, TdT, and myeloid (CD13, CD14, CD33) and megakaryocyte/platelet (CD36, CD41, CD42b, CDw49b) antigens. In short-term culture, UCSD/AML1 cells proliferate in response to interleukin-3 (IL-3), IL-4, IL-6, macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage CSF (GM-CSF), but not IL-1, IL-2, IL-5, or G-CSF. In long-term culture, proliferation can be sustained by GM-CSF, IL-6, or M-CSF. When maintained in GM-CSF, a small percentage of cells form multinucleated megakaryocyte-like giant cells. Culture with GM-CSF combined with IL-6, but not with IL-6 alone, increased giant cell formation fourfold to sevenfold. IL-6 alone or in combination with GM-CSF increased expression of platelet-related antigens. In contrast, culture with phorbol ester induced formation of macrophage-like cells. UCSD/AML1 is the first human acute nonlymphocytic leukemia cell line established from a patient with an acute leukemia syndrome associated with a specific chromosome abnormality.
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PMID:Characterization of a factor-dependent acute leukemia cell line with translocation (3;3)(q21;q26). 169 79

We investigated functional interactions between granulocyte-monocyte-colony-stimulating factor (GM-CSF) and the insulin family hormones using the GM-CSF- and insulin-dependent human acute myeloid leukemia cell line AML-193. Recombinant human GM-CSF and insulin enhanced AML-193 cell proliferation 3- and 5-fold, respectively, and showed a synergistic 10-fold increase when added in combination. Insulin-like growth factors I and II (IGFI and IGFII) increased AML-193 cell proliferation 4-fold and 2-fold, respectively, and also demonstrated synergy when combined with GM-CSF. Blocking experiments with monoclonal antibodies against the insulin and IGFI receptors indicated that the proliferative effects of insulin and IGFI were mediated through both their homologous and heterologous receptors. Pertussis toxin and cholera toxin, which ADP ribosylate GTP-binding proteins (G proteins), and the cyclic AMP analogue, dibutyryl cyclic AMP, decreased the proliferation induced by GM-CSF or insulin. Specific receptor binding of 125I-insulin, -IGFI, and -GM-CSF to AML-193 cells was demonstrated and not affected by preincubation with pertussis toxin or cholera toxin. Radiolabeled GM-CSF, insulin, and IGFI did not cross-compete with the heterologous ligands for receptor binding. These studies demonstrate (a) association between receptor binding and proliferative effects of GM-CSF and the insulin family hormones, (b) involvement of the G proteins in signal transduction provoked by these hormones which occurs at a postreceptor-binding level, and (c) synergistic mitogenic interactions between GM-CSF and the insulin family hormones, suggesting that their receptors are linked to divergent signaling mechanisms in addition to sharing G protein-coupled pathways.
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PMID:Functional interactions between colony-stimulating factors and the insulin family hormones for human myeloid leukemic cells. 169 37

In vitro proliferation of leukemic cells purified from 10 cases of acute myeloblastic leukemia (AML) was analyzed in basal conditions or in the presence of exogenous recombinant (r) Interleukin (IL) 1. In parallel, blasts from 5 of these patients were studied for granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte-CSF (G-CSF) mRNA. IL-1 augmented the spontaneous AML cell proliferation in all cases and induced de novo expression or increased amounts of GM-CSF and/or G-CSF transcripts in 4 of the 5 cases evaluated. IL-1-induced AML cell proliferation was modulated by neutralizing anti-GM-CSF or anti-G-CSF antibodies in those cases in which CSF mRNAs were induced or increased by exogenous cytokine. In the same cases, biosynthetic labelling and immunoprecipitation studies using monospecific anti-GM-CSF antibodies showed that IL-1 also increased the levels of GM-CSF protein synthesis. Addition of neutralizing anti-IL-1 antibodies to AML cell cultures completely abolished ongoing GM-CSF synthesis, suggesting that endogenous IL-1 is needed to maintain autocrine production of CSFs. The effects of rIL-2 were investigated in a larger series of 21 patients. The cytokine reduced spontaneous AML cell proliferation in 8 cases. It caused complete disappearance of GM-CSF mRNA in 1 case, and marked reduction of G-CSF mRNA in 2 cases. Increased AML cell proliferation was observed in 2 of 21 cases. These findings suggest that expression of CSF genes and cell proliferation in AML are under the control of different cytokines acting in autocrine or paracrine fashion.
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PMID:Interleukin-1 and interleukin-2 control granulocyte- and granulocyte-macrophage colony-stimulating factor gene expression and cell proliferation in cultured acute myeloblastic leukemia. 169 3

To determine the growth requirement of leukemic blast progenitors in acute myeloblastic leukemia (AML), leukemic cells from the peripheral blood of eight AML patients were cultured in the serum-free culture system. Blast progenitors made colonies in methylcellulose culture and showed exponential growth in suspension culture, although the growth of blast progenitors in the absence of fetal calf serum (FCS) in some patients was inferior to that in the FCS-enhanced culture system. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) stimulated the growth of blast progenitors in a dose-responsive manner. When cells were cultured at high cell density, blast colonies were formed even in the absence of CSF. Irradiated blasts also supported the growth of intact blast progenitors. These results confirm the finding noted in the FCS-enhanced culture studies that granulopoietic factor, G-CSF, plays an important role on the leukemic growth. The importance of cell to cell interaction for the growth of blast progenitors was also confirmed.
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PMID:Role of humoral and cellular factors on the growth of blast progenitors of acute myeloblastic leukemia in serum-free culture. 170 66

Upon treatment with the phorbol ester, tetradecanoylphorbol 13-acetate (PMA), peripheral mononuclear blood cells from patients with acute myeloid leukemia secrete into serum-free cell-conditioned media (PMA-CCM) at least three distinct nondialysable 'hematopoietic' factors: granulocyte-colony-stimulating factor (G-CSF), granulocyte/macrophage-colony-stimulating factor (GM-CSF) and erythroid differentiation factor (EDF, activin A). G-CSF was identified by its stimulation of [3H]thymidine incorporation into a G-CSF-responsive cell line, NSF-60, and the inhibition of its stimulation by a G-CSF-specific monoclonal antibody (MAB). GM-CSF was identified by its stimulation of [3H]thymidine incorporation into a GM-CSF-responsive line, TALL-101, and the inhibition of its stimulation by a GM-CSF-specific MAB. EDF was identified by its ability to stimulate erythroid differentiation in mouse erythroleukemia cell lines, its identical retention times to those of authentic EDF on three successive reverse-phase HPLC columns and characterization of its penultimate N-terminal residue as leucine which is the same as that of authentic EDF. Both authentic EDF and the erythroid-stimulating activity in PMA-CCM were found to act synergistically with a suboptimal inducing concentration of a well-studied inducing agent, dimethyl sulfoxide, in inducing erythroid differentiation. In addition, a fourth activity was observed in PMA-CCM: normal human fetal bone marrow cell-proliferation stimulating activity (FBMC-PSA). FBMC-PSA was identified by its ability to stimulate the growth of granulocytes and macrophages in FBMC suspension cultures, which neither recombinant G-CSF or GM-CSF were found to do.
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PMID:Phorbol ester-treated human acute myeloid leukemia cells secrete G-CSF, GM-CSF and erythroid differentiation factor into serum-free media in primary culture. 170 23

Tumor necrosis factor (TNF) inhibits granulocyte-colony-stimulating factor (G-CSF)-induced human acute myeloid leukemia (AML) growth in vitro. Incubation of blasts from three patients with AML in serum-free medium with TNF (10(3) U/ml), and subsequent binding studies using 125I-G-CSF reveal that TNF downregulates the numbers of G-CSF receptors by approximately 70%. G-CSF receptor numbers on purified blood granulocytes are also downmodulated by TNF. Downregulation of G-CSF receptor expression becomes evident within 10 min after incubation of the cells with TNF at 37 degrees C and is not associated with an apparent change of the dissociation constant (Kd). The TNF effect does not occur at 0 degrees C and cannot be induced by IL-2, IL-6, or GM-CSF. TNF probably exerts its effect through activation of protein kinase C (PKC) as the TNF effect on G-CSF receptor levels can be mimicked by 12-O-tetradecanoylphorbol-13- acetate. The PKC inhibitor Staurosporine (Sigma Chemical Co., St. Louis, MO) as well as protease inhibitors can completely prevent G-CSF receptor downmodulation. Thus, it appears TNF may act as a regulator of G-CSF receptor expression in myeloid cells and shut off G-CSF dependent hematopoiesis. The regulatory ability of TNF may explain the antagonism between TNF and G-CSF stimulation.
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PMID:Tumor necrosis factor downregulates granulocyte-colony-stimulating factor receptor expression on human acute myeloid leukemia cells and granulocytes. 170 66


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