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 beta-type receptor of platelet-derived growth factor (beta PDGFR) is a class III transmembrane receptor with tyrosine kinase activity. The beta PDGFR gene is located on mouse chromosome 18 close to the c-fms gene which codes for the colony stimulating factor-1 receptor (CSF-1R). We previously reported that in a high percentage of myeloblastic leukemias induced by the Friend helper murine leukemia virus (F-MuLV), proviruses were integrated in the first intron of the c-fms gene leading to an enhanced expression of c-fms mRNA. Since activation by proviral insertion can act at long distance, we studied beta PDGF receptor gene expression in murine myeloblastic leukemias. This gene was found to be frequently expressed but the level of beta PDGF receptor mRNA was weak and not related to proviral activation. High affinity binding sites were expressed on myeloblastic cells and ligand binding induced cell proliferation. To determine whether beta PDGFR expression is a common feature in hematopoietic cells, we tested cell lines belonging to other hematopoietic lineages. We found that multipotent stem and mast cell lines also expressed the beta PDGF receptor gene. This suggests that PDGF, known as a mitogen for connective tissue cells, could also play a role in normal hematopoiesis.
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PMID:Expression of functional beta-platelet-derived growth factor receptors on hematopoietic cell lines. 848 8

A pilot study was conducted of the biological characteristics of the leukemia cells of newly diagnosed patients with poor prognosis acute myelogenous leukemia (AML). This study included measurements of the pretherapy proliferative rate of the leukemia cells in vivo, assessment of differentiation in vivo during remission induction therapy, and the level of expression of the fms, myc, and IL1 beta genes in pretherapy leukemia cells. Short cell cycle times were characteristic of the best prognostic category and were associated with a rapid reduction in marrow leukemia cells in cytosine arabinoside (araC)-sensitive patients. Expression of c-fms was associated with rapid reduction in marrow leukemia cells during araC therapy and with a successful treatment outcome. Expression of the IL1 beta gene was associated with short remissions. These studies suggest that when compared to newly diagnosed standard prognosis AML, the leukemia of poor prognosis patients is more likely to exhibit long cell cycle times, low levels of fms expression, and is less likely to be associated with myeloid differentiation during remission induction therapy.
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PMID:Biological characteristics of newly diagnosed poor prognosis acute myelogenous leukemia. 849 86

The human interleukin-3 receptor (IL-3R) is expressed on myeloid, lymphoid, and vascular endothelial cells, where it transduces IL-3-dependent signals leading to cell activation. Although IL-3R activation may play a role in hematopoiesis and immunity, its aberrant expression or excessive stimulation may contribute to pathologic conditions such as leukemia, lymphoma, and allergic reactions. We describe here the generation and characterization of a monoclonal antibody (MoAb), 7G3, which specifically binds to the IL-3R alpha-chain and completely abolishes its function. MoAb 7G3 immunoprecipitated and recognized in Western blots the IL-3R alpha-chain expressed by transfected cells and bound to primary cells expressing IL-3R alpha. MoAb 7G3 bound the IL-3R alpha-chain with a kd of 900 pmol/L and inhibited 125I-IL-3 binding to high- and low-affinity receptors in a dose-dependent manner. Conversely, IL-3 but not granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited 125I-7G3 binding to high- and low-affinity IL-3Rs, indicating that MoAb 7G3 and IL-3 bind to common or adjacent sites. In keeping with the inhibition of IL-3 binding, MoAb 7G3 antagonized IL-3 biologic activities, namely stimulation of TF-1 cell proliferation, basophil histamine release, and IL-6 and IL-8 secretion from human endothelial cells. Two other anti-IL-3R alpha-chain MoAbs failed to inhibit IL-3 binding or function. Epitope mapping experiments using truncated IL-3R alpha-chain mutants and IL-3R alpha/GM-CSFR alpha chimeras revealed that 31 amino acids in the N-terminus of IL-3R alpha were required for MoAb 7G3 binding. MoAb 7G3 may be of clinical significance for antagonizing IL-3 in pathologic conditions such as some myeloid leukemias, follicular B-cell lymphoma, and allergy. Furthermore, these results implicate the N-terminal domain of IL-3R alpha in IL-3 binding. Since this domain is unique to the IL-3/GM-CSF/IL-5 receptor subfamily, it may represent a novel and common binding feature in these receptors.
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PMID:Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and functions as a specific IL-3 receptor antagonist. 854 80

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

The mRNA expression of alkaline phosphatase (ALP), myeloperoxidase (MPO), defensin and G-CSF receptor (G-CSFR) in bone marrow cells of normal individuals and myeloid disorders, with or without in vitro stimulation by myeloid cell growth factors, i.e. G-CSF, GM-CSF and IL-3, were examined as markers for myeloid cell differentiation in both mononuclear cell (MNC) and polymorphonuclear cell (PMN) fractions. Without any stimulation, ALP mRNA was expressed only in PMNs, G-CSFR mRNA in PMNs were expressed stronger than in MNCs; both MPO and defensin mRNA were expressed to the same degree in both fractions. With stimulation, the ALP mRNA expression in both fractions was strongly enhanced by G-CSF, but the expression was inhibited by GM-CSF and/or IL-3. MPO mRNA expression was stimulated by G-CSF and/or GM-CSF in MNCs. G-CSFR mRNA expression was enhanced by G-CSF in both fractions. Defensin mRNA expression was inhibited by G-CSF. In cases of myelodysplastic syndrome and chronic myelogenous leukaemia which display a suppressed maturation of myeloid cells, our results demonstrated an almost normal response to these growth factors. Our results suggest that studies on these myeloid marker mRNA expressions would provide more knowledge about the differentiation state and cytokine reactivity of myeloid cells in normal individuals as well as various disorders.
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PMID:Effects of myeloid cell growth factors on alkaline phosphatase, myeloperoxidase, defensin and granulocyte colony-stimulating factor receptor mRNA expression in haemopoietic cells of normal individuals and myeloid disorders. 856 17

The novel hematopoietic growth factor FLT3 ligand (FL) is the cognate ligand for the FLT3, tyrosine kinase receptor (R), also referred to as FLK-2 and STK-1. The FLT3R belongs to a family of receptor tyrosine kinases involved in hematopoiesis that also includes KIT, the receptor for SCF (stem cell factor), and FMS. the receptor for M-CSF (macrophage colony- stimulating factor). Restricted FLT3R expression was seen on human and murine hematopoietic progenitor cells. In functional assays recombinant FL stimulated the proliferation and colony formation of human hematopoietic progenitor cells, i.e. CD34+ cord and peripheral blood, bone marrow and fetal liver cells. Synergy was reported for co-stimulation with G-CSF (granulocyte-CSF). GM-CSF (granulocyte-macrophage CSF), M-CSF, interleukin-3 (IL-3), PIXY-321 (an IL-3/GM-CSF fusion protein) and SCF. In the mouse, FL potently enhanced growth of various types of progenitor/precursor cells in synergy with G-CSF, GM-CSF, M-CSF, IL-3, IL-6, IL-7, IL-11, IL-12 and SCF. The well-documented involvement of this ligand-receptor pair in physiological hematopoiesis brought forth the question whether FLT3R and FL might also have a role in the pathobiology of leukemia. At the mRNA level FLT3R was expressed by most (80-100%) cases of AML (acute myeloid leukemia) throughout the different morphological subtypes (MO-M7), of ALL(acute lymphoblastic leukemia) of the immunological subtypes T-ALL and BCP-ALL (B cell precursor ALL including pre-pre B-ALL, cALL and pre B-ALL), of AMLL (acute mixed-lineage leukemia), and of CML (chronic myeloid leukemia) in lymphoid or mixed blast crisis. Analysis of cell surface expression of FLT3R by flow cytometry confirmed these observations for AML (66% positivity when the data from all studies are combined), BCP-ALL (64%) and CML lymphoid blast crisis (86%) whereas less than 30% of T-ALL were FLT3R+. The myeloid, monocytic and pre B cell type categories also contained the highest proportions of FLT3R+ leukemia cell lines . In contrast to the selective expression of the receptor, FL expression was detected in 90-100% of the various cell types of leukemia cell lines from all hematopoietic cell lineages. The potential of FL to induce proliferation of leukemia cells in vitro was also examined in primary and continuously cultured leukemia cells. The data on FL-stimulated leukemia cell growth underline the extensive heterogeneity of primary AML and ALL samples in terms of cytokine-inducible DNA synthesis that has been seen with other effective cytokines. While the majority of T-ALL (0-33% of the cases responded proliferatively; mean 11%) and BCP-ALL (0-30%; mean 20%) failed to proliferate in the presence of FL despite strong expression of surface FLT3R, FL caused a proliferative response in a significantly higher percentage of AML cases (22-90%; mean 53%). In the panel of leukemia cell lines examined only myeloid and monocytic growth factor- dependent cell lines increased their proliferation upon incubation with FL, whereas all growth factor-independent cell lines were refractory to stimulation. Combinations of FL with G-CSF, GM-CSF, M-CSF, IL-3, PIXY- 321 or SCF and FL with IL-3 or IL-7 had synergistic or additive mitogenic effects on primary AML and ALL cells, respectively. The potent stimulation of the myelomonocytic cell lines was further augmented by addition of bFGF (basic fibroblast growth factor), GM-CSF, IL-3 or SCF. The inhibitory effects of TGF-beta 1 (transforming growth factor-beta 1) on FL- supported proliferation were abrogated by bFGF. Taken together, these results demonstrate the expression of functional FLT3R capable of mediating FL- dependent mitogenic signaling in a subset of AML and ALL cases further underline the heterogeneity of AML and ALL samples in their proliferative response to cytokine.
Leukemia 1996 Apr
PMID:Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. 861 33

Deletion mutants of the intracytoplasmic domain of the granulocyte colony stimulating factor receptor (G-CSFR) have shown that it contains a membrane-proximal region which must be conserved to allow the receptor to transduce a mitotic signal, and a C-terminal region necessary for transduction of cell differentiation. Changes in the intracytoplasmic domain may result in the uncoupling of these two processes, as in acute leukaemia, and such alterations could occur either as isoforms or mutations. We have studied the transmembrane domain and intracytoplasmic tail of the G-CSFR in RNA from blood or bone marrow of 11 haematologically normal controls and 40 patients with acute myeloid leukaemia (AML). Two novel transcripts of the receptor were identified, both were minor components and are unlikely to be of major physiological significance. We could find no evidence for altered levels of expression of these transcripts in the AML patients. In addition, only one point mutation was detected in the 40 patients screened by RT-PCR-SSCP, a C-->A substitution at nucleotide 2088 which changes a threonine to asparagine in the transmembrane domain and is probably a polymorphism. These results suggest that abnormalities in the G-CSFR are uncommon in AML.
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PMID:Analysis of granulocyte colony stimulating factor receptor isoforms, polymorphisms and mutations in normal haemopoietic cells and acute myeloid leukaemia blasts. 865 69

Granulocyte colony-stimulating factor (G-CSF) can elicit different biological responses through interaction with its receptor (G-CSFR). A series of G-CSFR expressing clones were established from WEHI-3B D+ myelomonocytic leukemia cells and interleukin-3 (IL-3) dependent Ba/F3 preB cells by transduction of a G-CSFR cDNA. The overexpression of the G-CSFR from the expression vector promoted differentiation in WEHI-3B D+ cells exposed to G-CSF, while, in contrast, the cytokine supported growth in Ba/F3 cells transfected with the expression plasmid in the absence of IL-3. Western blotting, immunoprecipitation and cell surface labeling with Na[125I] followed by immunoprecipitation with an anti-G-CSFR antibody revealed different patterns of detected proteins in these two cell lines, implying that different forms of the G-CSFR were generated which produced distinct biological responses and/or that different cell-type specific signal transducers were involved in the production of cellular differentiation or growth.
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PMID:Granulocyte colony-stimulating factor receptor mediated cell growth and differentiation. 870 76

Hematopoietic tyrosine kinase receptors (HGF-TKRs or class III TKRs) are essential for the growth and differentiation of hematopoietic cells. In this report we present a novel method that generates expression profiles of these receptors. The method was tested and optimized using the myeloblastic/ promyelocytic cell line KG1. The method involves PCR of cDNA using class III-specific degenerate primers and subsequent restriction enzyme digests of the 147 bp amplicons followed by fractionation on denaturing poly-acrylamide gels. This primary fingerprint of KG1 revealed equal expression of c-kit and flt3 and to a lesser extent PDGF-R alpha and c-fms. One residual band of unknown origin was seen and appeared to be the proto-oncogene RET following cloning and sequence analysis. This tyrosine kinase receptor is known to play an important role in neural development. In order to detect less abundantly expressed sequences, a secondary fingerprint was generated by pre-digestion of the receptors present in the primary expression profile and subsequent amplification of the residual band. No other tyrosine kinase receptors were observed in KG1. In conclusion, this method allows direct visualization of expression of the HGF-TKRs and has the potential to detect novel homologous receptors.
Leukemia 1996 Aug
PMID:Direct display of hematopoietic tyrosine kinase receptor expression profiles in KG1 cells by PCR using degenerate primers. 870 51

There is increasing evidence that the supportive cells (stromal cells) in nearly all organs containing cellular self-renewal systems are involved in carcinogenesis. One body of evidence specific to irradiation leukemogenesis documents the role of irradiated murine stromal cells in the cell biologic changes associated with evolution of leukemia in cocultivated, nonirradiated stem cells. Stem cell phenotypic changes that have been documented include upregulation of cell surface c-fms, downregulation of growth requirement for obligatory growth factors, and the appearance of novel transcripts detected by differential display. A second body of evidence documents the potential role of stromal cells functioning as biologic tumor promoters through their release of reactive oxygen species (ROS), and production of altered adhesion molecules or growth factors during the chronic response to chemical or physical carcinogens. These molecular biologic mechanisms, potentially operative in stromal cells, can block apoptosis and induce DNA strand breaks in closely associated self-renewing stem cells. In an in vivo model of irradiation effects on lung stromal cells, we have irradiated the lungs of control C57BL/6J mice or other mice with orthotopic Lewis lung tumors and shown that TGF-beta release is increased following irradiation. The TGF-beta increase by irradiation may specifically be inhibited by administering an inhalation plasmid liposome mixture containing a transgene for human manganese superoxide dismutase prior to irradiation. An appreciation of the role of stromal cells in leukemogenesis and carcinogenesis may also be very relevant to the design of new therapeutic strategies for treatment of cancer, particularly since current strategies focus on eradication of stem cell transformants and do not rigorously address the persistence of surviving stromal cells.
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PMID:Stromal cell involvement in leukemogenesis and carcinogenesis. 872 6


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