UMLS:C0598766 - FACTA Search

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Query: UMLS:C0598766 (leukemogenesis)
4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the NF-kappa B/Rel family of transcription factors are involved in the transcriptional regulation of numerous polypeptides important to the immune response and cellular growth. Several genes regulated in part by NF-kappa B/Rel such as interleukin 2, IL-2 receptor alpha, and GM-CSF are trans-activated via an indirect association with the HTLV-I Tax protein in virus-infected and transformed T cells. In this study, we have investigated the interactions between Tax and NF-kappa B/Rel in an attempt to elucidate the mechanism of Tax mediated trans-activation and its role in leukemogenesis. Transfection studies were performed in Jurkat T cells using expression vectors for individual NF-kappa B subunits and the Tax protein as well as an NF-kappa B regulated reporter plasmid. NF-kappa B proteins differentially trans-activated the HIV-1 enhancer-CAT reporter; co-expression of Tax abrogated the inhibitory effect of I kappa B alpha and a trans-dominant negative mutant of p65 (p65 delta), indicating that Tax was a trans-dominant activator of NF-kappa B-regulated genes. Co-immunoprecipitation studies with extracts from transfected cells and NF-kappa B and Tax subunit specific antibodies revealed that Tax did not co-immunoprecipitate with p50/p105, c-Rel, or I kappa B; however, antibody specific to p65 was able to co-immunoprecipitate a 40kDa protein from Tax-transfected cells. Previous studies have demonstrated a physical interaction between Tax protein and p100, indicating that Tax may preferentially associate with specific NF-kappa B proteins.
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PMID:Interactions between HTLV-I Tax and NF-kappa B/Rel proteins in T cells. 815 9

Interstitial deletions of the long arm of chromosome 5 are common in a number of disorders of leukemic and preleukemic myeloid disorders. Although the limits of these deletions vary among patients, a region of cytogenetic overlap that includes band 5q31 is deleted consistently, suggesting loss of 5q31 loci critical for normal myeloid differentiation and leukemogenesis. An anonymous genomic DNA segment D5S89, previously mapped to 5q21-31, detects consistent loss of alleles in cases showing the 5q- chromosome at presentation or relapse. Analysis of a panel of natural-deletion somatic-cell hybrids in conjunction with irradiation hybrids containing fragments of human chromosome 5q shows that the D5S89 locus is telomeric to the interleukin (IL) genes (IL-3, IL-4, IL-5, IL-9, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) and interferon response factor-1 (IRF-1) gene and centromeric to the early response transcription factor (early growth response gene-1 [EGR-1]) on 5q31. To further define the principal region of loss, we have isolated and characterized yeast artificial chromosomes (YACs) spanning D5S89. The presence of several CpG islands within the 300-kb YAC is suggestive of multiple transcription units. However, IL-4, IL-5, IRF-1, IL-3, GM-CSF, and EGR-1 genes were not detected in the YAC clone spanning D5S89, implying that none of these genes are in the vicinity of the D5S89 marker. Further characterization of these YACs should facilitate the isolation of novel candidate genes that may play a role in the evolution of the abnormal phenotype associated with 5q- chromosome.
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PMID:Consistent loss of the D5S89 locus mapping telomeric to the interleukin gene cluster and centromeric to EGR-1 in patients with 5q- chromosome. 827 35

In tissues such as bone marrow with normally high rates of cell division, proliferation is tightly coordinated with cell differentiation. Survival, proliferation and differentiation of early hematopoietic progenitor cells depend on the growth factors, interleukin 3 (IL-3) and/or granulocyte-macrophage colony stimulating factor (GM-CSF) and their synergism with other cytokines. We provide evidence that a characteristic shared by a diverse group of compounds with demonstrated leukemogenic potential is the ability to act synergistically with GM-CSF. This results in an increase in recruitment of a resting population of hematopoietic progenitor cells normally unresponsive to the cytokine and a twofold increase in the size of the proliferating cell population normally regarded to be at risk of transformation in leukemogenesis. These findings support the possibility that transient alterations in hematopoietic progenitor cell differentiation may be an important factor in the early stages of development of leukemia secondary to chemical or drug exposure.
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PMID:Cell proliferation and differentiation in chemical leukemogenesis. 831 10

We have used a human GM-CSF-dependent hematopoietic cell line that responds to physiological concentrations of hGM-CSF to analyze a set of signaling events that occur in normal myelopoiesis and whose deregulation may lead to leukemogenesis. Stimulation of these cells with hGM-CSF induced the assembly of multimeric complexes that contained known and novel phosphotyrosyl proteins. One of the new proteins was a major phosphotyrosyl substrate of 76-85 kDa (p80) that was directly associated with the p85 subunit of phosphatidylinositol (PI) 3-kinase through the SH2 domains of p85. p80 also associated with the beta subunit of the activated hGM-CSF receptor, and assembly of this complex correlated with activation of PI 3-kinase. A second phosphotyrosyl protein we identified, p140, associated with the Shc and Grb2 adapter proteins by direct binding to a novel phosphotyrosine-interacting domain located at the N-terminus of Shc. and to the SH3 domains of Grb2, respectively. The Shc/p140/Grb2 complex was found to be constitutively activated in acute myeloid leukemia cells, indicating that activation of this pathway may be a necessary step in the development of some leukemias. The p80/p85/PI 3-kinase and the Shc/Grb2/p140 complexes were tightly associated with Src family kinases, which were prime candidates for phosphorylation of Shc, p80, p140 and other phosphotyrosyl substrates present in these complexes. Our studies suggest that p80 and p140 may link the hGM-CSF receptor to the PI 3-kinase and Shc/Grb2/ras signaling pathways, respectively, and that abnormal activation of hGM-CSF-dependent targets may play a role in leukemogenesis.
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PMID:Novel adapter proteins that link the human GM-CSF receptor to the phosphatidylino-sitol 3-kinase and Shc/Grb2/ras signaling pathways. 858 65

The survival, proliferation, differentiation and function of normal hematopoietic cells are negatively and positively controlled by various cytokines. Survival and proliferation of leukemic cells appears to be influenced, at least in vitro, by several cytokines. Among the different hematopoietic cell lineages, megakaryocytopoiesis represents a complex and unique hematopoietic system that is thought to be supported by some well-known cytokines; however, the hypothetical lineage-specific main regulator of platelet production, termed thrombopoietin (TPO) had remained elusive. Recently, characterization of the proto-oncogene c-mpl revealed structural homology with the hematopoietic cytokine receptor superfamily, specific expression on cells of the megakaryocytic lineage and functional involvement in megakaryocytopoiesis. Several groups purified and cloned the MPL ligand. Extensive in vitro and in vivo studies have shown that the MPL ligand has activity in stimulating both megakaryocytopoiesis and platelet production proving that this ligand is the long-sought growth factor TPO itself. The MPL receptor was found at the mRNA and/or protein level in 40-80% of primary acute myeloid leukemia (AML) cases in various series. MPL expression was not limited to certain morphological FAB types, although the highest percentages were seen in the M6 (erythroid) and M7 (megakaryocytic) subclasses. Among the myelodysplastic syndromes (MDS), MPL expression was detected in one third of the cases, in particular in refractory anemia with excess of blasts and chronic myelomonocytic leukemia. Lymphoid malignancies such as acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and myeloma were MPL-negative. Among the large panel of human leukemia-lymphoma cell lines studied, MPL expression occurred predominantly in lines with erythro-megakaryocytic phenotypes. Nearly all primary and continuously cultured non-hematopoietic solid tumor samples were negative for MPL expression. A significant portion of AML cases and of erythroid, megakaryocytic and myeloid leukemia cell lines co-expressed TPO and MPL mRNA transcripts, although no biologically active TPO appeared to be secreted by these cells. In several studies TPO induced in vitro proliferation of 14-37% of primary AML cases, predominantly of the M2 and M7 subtypes. TPO significantly enhanced the cytokine-induced growth of AML cells in a substantial fraction of cases responsive to GM-CSF, IL-3, IL-6 or SCF. While none of 30 growth factor-independent erythro-megakaryocytic leukemia cell lines responded to TPO with increased proliferation, TPO strongly augmented the growth of several constitutively cytokine-dependent cell lines (eg HU-3, M-07e, TF-1) which can be made TPO-dependent and used as bioassays. Neither in primary cells nor in cell lines did TPO appear to induce any signs of morphological, functional or immunological differentiation. Expression of the MPL receptor is not correlated with a proliferative response to TPO. In summary, extensive studies on normal human and animal cells demonstrated the specificity and function of the MPL receptor and proved that its ligand TPO is the major physiological regulator of megakaryocytopoiesis. The data reviewed here document the wide expression of the MPL receptor on AML cells and also suggest some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic AML cells as well. Thus, experimental evidence supports the notion that TPO may contribute, at least in part, to leukemogenesis, especially in combination with other hematopoietic cytokines which is of clinical significance. TPO-responsive cell lines represent powerful tools for such analyses.
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PMID:Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells. 875 57

In the early stages of the development of granulocytic colony-stimulating factors (G-CSF and GM-CSF) in oncology and hematology, myeloid malignancies were considered to be a contraindication to their use. In fact, myeloid leukemic cells bear specific receptors for G-CSF and GM-CSF and these CSFs induce an in vitro proliferation in primary blast cells of most patients with acute myeloid leukemia (AML). In addition, autocrine or paracrine loops of stimulation have been demonstrated in some cases. Despite these theoretical risks of blast proliferation, G-CSF and GM-CSF have been extensively tested in patients with AML or myelodysplastic syndromes. Major objectives were the correction of acquired or chemotherapy-induced neutropenia, but also the reinforcement of the antileukemic efficacy of cytotoxic agents. Recently, G-CSF has also been used to mobilize hematopoietic progenitors in the peripheral blood. Major results of several double-blind clinical trials are the demonstration of the safety of CSF administration in these patients, since no risk of in vivo blast cell regrowth has been observed, and their efficacy to shorten the duration of chemotherapy-induced neutropenia. However, no significant reduction in the treatment-related mortality and no survival improvement were afforded by the use of these CSFs. From another point of view, the search for AML-specific CSF-receptor or CSF-receptor associated molecule abnormalities represents a new promising area to try to understand the mechanisms of leukemogenesis.
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PMID:Granulocytic colony-stimulating factors in the management of patients with acute myeloid leukemia. 897 86

The normal proto-oncogene c-fms encodes the macrophage growth factor (M-CSF) receptor involved in growth, survival, and differentiation along the monocyte-macrophage lineage of hematopoietic cell development. A major portion of our research concerns unraveling the temporal, molecular, and structural features that determine and regulate these events. Previous results indicated that c-fms can transmit a growth signal as well as a signal for differentiation in the appropriate cells. To investigate the role of the Fms tyrosine autophosphorylation sites in proliferation vs. differentiation signaling, four of these sites were disrupted and the mutant receptors expressed in a clone derived from the myeloid FDC-P1 cell line. These analyses revealed that: (1) none of the four autophosphorylation sites studied (Y697, Y706, Y721, and Y807) are essential for M-CSF-dependent proliferation of the FDC-P1 clone; (2) Y697, Y706, and Y721 sites, located in the kinase insert region of Fms, are not necessary for differentiation but their presence augments this process; and (3) the Y807 site is essential for the Fms differentiation signal: its mutation totally abrogates the differentiation of the FDC-P1 clone and conversely increases the rate of M-CSF-dependent proliferation. This suggests that the Y807 site may control a switch between growth and differentiation. The assignment of Y807 as a critical site for the reciprocal regulation of growth and differentiation may provide a paradigm for Fms involvement in leukemogenesis, and we are currently investigating the downstream signals transmitted by the tyrosine-phosphorylated 807 site. In Fms-expressing FDC-P1 cells, M-CSF stimulation results in the rapid (30 sec) tyrosine phosphorylation of Fms on the five cytoplasmic tyrosine autophosphorylation sites, and subsequent tyrosine phosphorylation of several host cell proteins occurs within 1-2 min. Complexes are formed between Fms and other signal transduction proteins such as Grb2, Shc, Sos1, and p85. In addition, a new signal transduction protein of 150 kDa is detectable in the FDC-P1 cells. The p150 is phosphorylated on tyrosine, and forms a complex with Shc and Grb2. The interaction with Shc occurs via a protein tyrosine binding (PTB) domain at the N-terminus of Shc. The p150 is not detectable in Fms signaling within fibroblasts, yet the PDGF receptor induces the tyrosine phosphorylation of a similarly sized protein. In hematopoietic cells, this protein is involved in signaling by receptors for GM-CSF, IL-3, KL, MPO, and EPO. We have now cloned a cDNA for this protein and found at least one related family member. The related family member is a Fanconia Anemia gene product, and this suggests potential ways the p150 protein may function in Fms signaling.
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PMID:Growth and differentiation signals regulated by the M-CSF receptor. 898 70

Although severe combined immunodeficient (SCID) mice are considered useful as an animal model for human hematopoietic diseases, the complete reconstruction of human hematopoietic cells can not be established even in these mice. This appears to be because human cytokines, adhesion molecules and extracellular matrices which support differentiation and growth of human hematopoietic cells differ from those in animals. To improve this animal model, we attempted to produce transgenic (Tg) mice producing human interleukin 3 (hIL-3) and human granulocyte macrophage colony stimulating factor (hGM-CSF) with the homozygote of the scid gene. We established two Tg mouse lines, one releasing both 0.5-1 ng/ml of hIL-3 and 0.05-0.2 ng/ml of hGM-CSF in their sera and another releasing only high (2-10 ng/ml) levels of hGM-CSF. When human cytokine-dependent myeloid cell line, TF-1, was subcutaneously transplanted into these two Tg-SCID mouse lines, TF-1 could be successfully engrafted and grew in all lines of Tg-SCID mice but not in control mice. We also observed that TF-1 grows in GM-CSF Tg-SCID mice in a dose dependent manner in vivo and IL-3 shows an additive effect on its growth. These results indicated that these Tg-SCID mice were an useful in vivo model for investigating human leukemogenesis, especially the role of IL-3 and GM-CSF in leukemogenesis.
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PMID:Cytokine dependent growth of human TF-1 leukemic cell line in human GM-CSF and IL-3 producing transgenic SCID mice. 971 16

FLT3 ligand (FL) acting through its tyrosine kinase receptor FLT3 has pleiotropic and potent effects on hematopoietic cells. The well-described involvement of this ligand-receptor pair in physiological hematopoiesis raised the question whether FL and FLT3 also play a role in the pathobiology of leukemia. Following the early discovery of high receptor expression by myeloid leukemia cells, several investigators have focused their attention on these cells, both primary acute myeloid leukemia (AML) cells and continuous human myeloid leukemia cell lines. Regardless of the morphological FAB subtype, the vast majority of AML cases were FLT3-positive both at the mRNA and protein level; among the myeloid cell lines, predominantly the monocytic and myelocytic cell lines were FLT3-positive whereas the erythrocytic and megakaryocytic cell lines were FLT3-negative. Virtually all cell lines studied expressed FL transcripts; the finding that some cell lines displayed both ligand and receptor indicates the possibility of autocrine, intracrine or paracrine stimulatory loops. In vitro growth assays showed that FL caused a proliferative response in a high percentage of AML cases. Only constitutively growth factor-dependent myelocytic cell lines increased their proliferation upon incubation with FL whereas all growth factor-independent cell lines were refractory to FL stimulation. Combinations of FL with various cytokines (e.g. G-CSF, GM-CSF, IL-3, M-CSF, PIXY-321, SCF) had synergistic or additive mitogenic effects. Finally, FL had significant anti-apoptotic, survival-promoting effects on primary AML cells and myeloid cell lines under serum-free culture conditions. On the strength of the above findings, it can be concluded that the FL-FLT3 signaling system may play a certain, albeit probably not causal role in the development of human leukemias. Dissection of the exact molecular pathways that lead to proliferation and/or anti-apoptosis of myeloid leukemia cells as well as the detailed elucidation of the possible contribution of the FL-FLT3 genes to leukemogenesis remain future challenges.
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PMID:Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells. 1019 24

Mutational activation of RAS is the most common molecular abnormality in myeloid leukemias. In order to better understand its role in leukemogenesis, we have devised a model based on the multipotent cell line, FDCP-mix. We show that expression of mutant RAS in FDCP-mix strongly inhibits terminal neutrophil differentiation under the influence of G-CSF plus GM-CSF at the metamyelocyte stage, whereas macrophage differentiation was unaffected. In addition, whereas control cultures differentiated and became postmitotic under these conditions, FDCP-mix cells expressing mutant RAS continued to proliferate indefinitely while maintaining a metamyelocytic phenotype. Labeling of these cultures with the fluorescent tracking dye, PKH26, showed that this extended proliferative capacity resulted from continued division of metamyelocytes in the culture. Dissection of the growth factor response of these cells demonstrated that GM-CSF was critical in maintaining proliferation and inhibiting the differentiation of these cells. We further show the block in neutrophil differentiation could be partially overcome by treatment with low-dose Ara C, suggesting that maintenance of cell cycle progression may be partly responsible for the anti-differentiation effect of this oncogene. These findings suggest that activation of RAS is able to specifically inhibit terminal neutrophil differentiation and in so doing promotes continued division of metamyelocyte cells.
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PMID:Mutant RAS inhibits neutrophil but not macrophage differentiation and allows continued growth of neutrophil precursors. 1056 Sep 7

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