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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biologic response of the human leukemia cell line M-07 to granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3) and interleukin 4 (IL-4) is mediated by a low number of high affinity receptors. Cross-competition studies revealed that IL-3 and GM-CSF partially inhibited the specific binding of the heterologous radiolabeled ligand, whereas IL-4 binding was not affected by these cytokines. The molecular mechanism of cross-competition was investigated by chemical crosslinking and immunoprecipitation. Trimolecular receptor complexes consisting of a major 73kDa and two minor 120 and 128kDa membrane proteins for IL-3, and a major 84kDa and two minor 120 and 130 kDa proteins for GM-CSF were found on M-07 cells. The 73 and 84kDa proteins represent distinct and non-linked membrane proteins and are identical with the cloned, low affinity IL-3 and GM-CSF receptor proteins (Gearing et al, 1989, Hayashida et al, 1990). The higher molecular weight proteins share common binding sites as evidenced by immunoprecipitation of double-crosslinked membranes. The 120/128kDa proteins are most likely identical with the recently cloned and shared beta-subunit of the IL-3 and GM-CSF receptor (Kitamura et al, 1991) containing a single or two IL-3 and/or GM-CSF molecules.
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PMID:Evidence for shared receptor proteins for human interleukin-3 and granulocyte-macrophage colony-stimulating factor in the human M-07 cell line. 845 May 10

Blast colony assays were performed on freshly obtained bone marrow samples from 19 newly diagnosed or relapsed children with acute lymphoblastic leukemia (ALL) of B lineage to determine the effect of added granulocyte-monocyte colony-stimulating factor (GM-CSF). Of the 19 marrow samples tested, 7 responded to GM-CSF with a mean increase in ALL blast colonies of 346%. Blast cells from one of the responders chosen for flow cytometric study showed expression of GM-CSF receptors on 38% of cells. These findings prompted us to establish five ALL cell lines of diverse phenotypes to examine the expression of GM-CSF and GM-CSF receptor genes in human leukemia, and to determine the role of GM-CSF in autocrine and paracrine growth control of ALL cells. One line, termed G2, manifested a GM-CSF-mediated autocrine pattern of cell growth with the following features: G2 blast colony growth in a serum-free system without added growth factor was density dependent; exogenous GM-CSF augmented G2 colony formation when the cells were seeded at low density; G2 cells constitutively expressed mRNA for GM-CSF and GM-CSF receptor; G2 cells also produced and secreted measurable amounts of GM-CSF into cell culture supernatant; and, monoclonal anti-GM-CSF antibodies abolished G2 colony growth when added to cultures with cells seeded at low density without growth factors. Of the other four ALL cell lines, three expressed mRNA for GM-CSF receptor and responded in vitro to added GM-CSF with increased blast colony growth; however, none of these four cell lines expressed mRNA for constitutive production of GM-CSF. A fifth ALL cell line lacked receptors for GM-CSF and did not respond in clonogenic assays to added GM-CSF. Thus, a bioregulator of normal hematopoiesis plays a central role in autocrine growth control of G2 ALL cells, and an important paracrine growth-promoting role in three of four other ALL cell lines.
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PMID:Autocrine and paracrine growth control by granulocyte-monocyte colony-stimulating factor of acute lymphoblastic leukemia cells. 849 41

Haemopoietic cytokines regulate haemopoietic cell function via specific cell surface receptors. These receptors are members of a large superfamily of transmembrane proteins and are characterised by a 200 amino acid extracellular sequence encoding the ligand binding domain. Several of the genes for members of this superfamily have now been characterised at the molecular level revealing a highly conserved organisation and a number of these genes have been localised cytogenetically. The recent finding that genes for the IL-3 and GM-CSF receptor alpha chain subunits colocalise to a small region of the pseudoautosomal region and the observation that the LIF receptor locus is present in a cluster of receptor genes on chromosome 5 suggest the possibility that subsets of cytokine receptor genes may be organised into clusters. This possibility is discussed and the potential significance of cytokine receptor gene clusters is assessed. Several of the receptor genes are known to be involved in inherited disorders and there is evidence to suggest lesions in cytokine receptor genes could have a role in leukaemia. We review the gene organisation, localisation and involvement in disease for the known cytokine receptor loci. This large family of receptors is expanding with the steady discovery of new members--all of which have the potential to be involved in human disorders.
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PMID:Cytokine receptor genes: structure, chromosomal location, and involvement in human disease. 852 43

The intracytoplasmic tail of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) beta c chain is essential for the activation of ligand-mediated signal transduction pathways in myeloid cells. Alterations in this region could deregulate normal signalling processes. We have therefore used RT-PCR-SSCP analysis of the receptor tail to look for point mutations in RNA from 35 patients with acute myeloid leukaemia (AML) and 10 haematologically normal controls. Patterns differing from those of the haemopoietic cell line TF-1 were detected in 25/35 (71%) AML patients and 8/10 (80%) normal controls. A total of six base substitutions were identified by sequencing. Three were conservative for the amino acid involved, three led to amino acid differences, valine652-->methionine, glycine647-->valine and proline603-->threonine. One alteration was found only in a normal control, the other five were all found in both AML patients and normal controls suggesting that they were DNA polymorphisms. Two substitutions were particularly common with allele frequencies of 0.23 (G1972-->A, unchanged proline648) and 0.13 (C1306-->T, unchanged serine426). These results indicate that the GM-CSFR beta c chain is highly polymorphic but point mutations of the intracytoplasmic tail do not appear to contribute frequently to the pathogenesis of AML.
Leukemia 1996 Jan
PMID:The beta subunit common to the GM-CSF, IL-3 and IL-5 receptors is highly polymorphic but pathogenic point mutations in patients with acute myeloid leukaemia (AML) are rare. 855 16

Normal expression of the hematopoietic growth factor receptor FLT3 (STK-1@Flk2) is limited to CD34+ stem/progenitor cells. We have evaluated the expression of FLT3 by RNase protection assay and Western blotting in 161 primary bone marrow (BM) samples from patients with leukemia. FLT3 RNA was found to be expressed at a higher level than in normal BM controls in 33 of 33 B-lineage acute leukemias, 11 of 12 acute myeloid leukemias (AMLs), and 3 of 11 T-cell acute leukemias (T-ALLs). Expression of FLT3 RNA was also observed in some cases of blast crisis CML. The FLT3 signal resulted from expression on the leukemic blasts, and was not caused by increased FLT3 expression on normal CD34+ stem/progenitor cells in the leukemic samples. To determine if FLT3 protein was also overexpressed, proteins were extracted from leukemic BM samples and screened by Western blotting with anti-FLT3 antisera. FLT3 protein was not detected in normal BM controls, but was found in 14 of 14 B-lineage ALLs, 36 of 41 AMLs, and 1 of 4 T-ALLs. Stimulation of patient samples with FLT3 ligand resulted in autophosphorylation of the FLT3 receptor, suggesting the receptor is functional in these cells. These data show that FLT3 RNA and protein are aberrantly expressed by AML and ALL cells in that CD34 expression and FLT3 expression are no longer synchronous, and suggest the possibility that overexpression of FLT3 could play a role in the survival and/or proliferation of malignant clones in acute myeloid and lymphoid leukemias.
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PMID:Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. 856 34

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) binds to a high-affinity heterodimeric receptor composed of a specific alpha chain and a common beta chain (beta(c)), which is shared with the receptors for interleukins 3 and 5. Hemopoietic cell survival requires GM-CSF binding this high-affinity receptor. We have recently developed the GM-CSF mutant E21R, which selectively binds to the alpha chain and behaves as a competitive GM-CSF antagonist. We have now examined the role of E21R on the survival of hemopoietic cells and found that E21R causes apoptosis (programmed cell death) of normal and malignant cells directly in the absence of GM-CSF. The direct apoptotic effect of E21R occurred in a dose- and time-dependent manner. Apoptosis by E21R was dependent on cells expressing the high-affinity GM-CSF receptor and could be blocked by GM-CSF. Significantly, apoptosis of the cells occurred even in the presence of the survival factors granulocyte CSF and stem cell factor but was prevented by engagement of beta(c) with interleukin 3. The initiation of apoptosis required phosphorylation, transcriptional activity, and protein synthesis. These findings support a model whereby binding of E21R to the alpha chain leads to apoptosis, while beta(c) plays an important role in cell survival. This model may be applicable to other multimeric cytokine receptors and offers a novel approach for the treatment of human leukemia.
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PMID:Apoptosis of hemopoietic cells by the human granulocyte-macrophage colony-stimulating factor mutant E21R. 861 Jan 18

Transcription factors play a key role in the development and differentiation of specific lineages from multipotential progenitors. Identification of these regulators and determining the mechanism of how they activate their target genes are important for understanding normal development of monocytes and macrophages and the pathogenesis of a common form of adult acute leukemia, in which the differentiation of monocytic cells is blocked. Our previous work has shown that the monocyte-specific expression of the macrophage colony-stimulating factor (M-CSF) receptor is regulated by three transcription factors interacting with critical regions of the M-CSF receptor promoter, including PU.1 and AML1.PU.1 is essential for myeloid cell development, while the AML1 gene is involved in several common leukemia-related chromosome translocations, although its role in hematopoiesis has not been fully identified. Along with AML1, a third factor, Mono A, interacts with a small region of the promoter which can function as a monocyte-specific enhancer when multimerized and linked to a heterologous basal promoter. Here, we demonstrate by electrophoretic mobility shift assays with monocytic nuclear extracts, COS-7 cell-transfected factors, and specific antibodies that the monocyte-enriched factor Mono A is CCAAT enhancer-binding protein (C/EBP). C/EBP has been shown previously to be an important transcription factor involved in hepatocyte and adipocyte differentiation; in hematopoietic cells, C/EBP is specifically expressed in myeloid cells. In vitro binding analysis reveals a physical interaction between C/EBP and AML1. Further transfection studies show that C/EBP and AML1 in concert with the AML1 heterodimer partner CBF beta synergistically activate M-CSF receptor by more then 60 fold. These results demonstrate that C/EBP and AML1 are important factors for regulating a critical hematopoietic growth factor receptor, the M-CSF receptor, suggesting a mechanism of how the AML1 fusion protein could contribute to acute myeloid leukemia. Furthermore, they demonstrate physical and functional interactions between AML1 and C/EBP transcription factor family members.
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PMID:CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. 862 67

Juvenile myelomonocytic leukemia (JMML) is a malignancy that almost inevitably leads to death before adulthood. Chemotherapy has given disappointing results and a substantial number of patients relapse after bone marrow transplantation. A salient feature of this disease is that the JMML cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF) spontaneously and survive and proliferate without exogeneous GM-CSF. Furthermore, JMML cells are hypersensitive to GM-CSF with addition of this cytokine leading to enhanced proliferation. We have recently generated a human GM-CSF analogue, E21R, that acts as a complete and selective GM-CSF receptor antagonist. We have now tested this molecule as a potential new agent to control the leukemic cell load in JMML with particular emphasis on its role in JMML cell survival. We found that E21R inhibited the spontaneous growth of JMML cells in vitro and caused their apoptosis in a dose- and time-dependent manner in seven of seven cases. In contrast, neither a neutralizing anti-GM-CSF monoclonal antibody (MoAb) nor a selective interleukin-1 (IL-1) receptor antagonist affected JMML cell survival. Furthermore, the apoptotic effect of E21R was seen even in the presence of interleukin-1 beta and tumor necrosis factor-alpha, which have also been implicated in the pathogenesis of JMML. The inhibitory effects of E21R on JMML cell growth and viability offer a novel approach to therapy in this lethal childhood leukemia.
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PMID:Inhibition of proliferation and induction of apoptosis in juvenile myelomonocytic leukemic cells by the granulocyte-macrophage colony-stimulating factor analogue E21R. 883 57

Interleukin-5 (IL-5), IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibit similar functions on eosinophils, and these common functions are believed to be mediated by the shared beta chain of receptors. IL-5 shows activity on the murine chronic B cell leukemia cell line BCL1-B20, inducing differentiation into IgM-secreting cells, but IL-3 and GM-CSF do not have such activity. To elucidate whether the lineage specificity of IL-5 is due to restricted expression of the IL-5 receptor alpha chain (IL-5R alpha), transfectants of BCL1-B20 were established that express IL-3 receptor alpha (BCL1-3R) or GM-CSF receptor alpha (BCL1-GMR). BCL1-3R and BCL1-GMR acquired responsiveness to IL-3 and GM-CSF, respectively, to an extent similar to IL-5 stimulation, resulting in IgM-secreting cells. Thus, the differentiation of BCL1-B20 into IgM-secreting cells can be equally supported by either IL-3 or GM-CSF, suggesting that intracellular signaling through IL-5R can be replaced by signaling from IL-3R and GM-CSFR. These results support the notion that the lineage specificity of IL-5 is mainly due to the restricted expression of IL-5R alpha. Regulation of IL-5R alpha, IL-3R alpha and GM-CSFR alpha expression in the developmental stage appears to be important for understanding the unique function of these cytokines on a particular cell type.
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PMID:Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce differentiation of chronic B cell leukemia expressing the alpha subunit of IL-3 and GM-CSF receptor. 890 4

The granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) is a potential target for toxin-directed therapy, because it is overexpressed on many leukemias and solid tumors and apparently not on stem cells. To investigate the potential therapeutic use of GM-CSF toxins, we fused human GM-CSF to truncated forms of either Pseudomonas exotoxin (PE) or diphtheria toxin (DT) and tested the cytotoxicity of the resulting GM-CSF-PE38KDEL and DT388-GM-CSF on human gastrointestinal (GI) carcinomas and leukemias. Toward gastric and colon cancer cell lines, GM-CSF-PE38KDEL was much more cytotoxic than DT388-GM-CSF, with IC50s (concentration resulting in 50% inhibition of protein synthesis) of 0.5 to 10 ng/mL compared with 4 to 400 ng/mL, respectively. In contrast, toward leukemia lines and fresh bone marrow cells DT388-GM-CSF was more cytotoxic than GM-CSF-PE38KDEL. The cytotoxicity of both GM-CSF-PE38KDEL and DT388-GM-CSF toward the human cells was specific, because it could be competed by an excess of GM-CSF. Binding studies indicated that human GM-CSF receptors were present on all of the human GI and leukemic cell lines tested, at levels of 540 to 3,700 sites per cell (kd = 0.2 to 2 nmol/L), and the number of sites per cell did not correlate with the cell type. A similar pattern of cytotoxicity was found with recombinant immunotoxins binding to the transferrin receptor, in that anti-TFR(Fv)-PE38KDEL was much more cytotoxic than DT388-anti-TFR(Fv) toward GI cells, but both were similar in their cytotoxic activity toward leukemia cells. The fact that PE is more effective than DT in killing GI but not leukemic tumor cells targeted by GM-CSF indicates a fundamental difference in the way PE or DT gains access to the cytosol in these cells. GM-CSF-PE38KDEL and DT388-GM-CSF deserve further evaluation as possible treatments for selected tumors.
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PMID:Recombinant toxins containing human granulocyte-macrophage colony-stimulating factor and either pseudomonas exotoxin or diphtheria toxin kill gastrointestinal cancer and leukemia cells. 920 60


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