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

The in vitro action of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D arabinofuranosylcytosine (ara-C) was studied on the human leukemia cell line U 937. Parameters investigated included monitoring of transcript levels of the proto-oncogenes C-MYC, C-FOS, and C-FMS, and analysis of nitroblue tetrazolium (NBT) reduction and of surface expression of the C3 bi receptor. Furthermore clonal proliferation of U 937 cells was assessed in soft agar cultures. The results indicate that both agents have only little effects on U 937 cells when acting alone. When combined in culture, however, they synergize to induce monocytic differentiation of U 937 cells as disclosed by significant increase of cells capable of reducing NBT and displaying surface C3 bi receptor that was accompanied by reduction of clonogenicity in colony assays. Induction of differentiation and inhibition of proliferation of U 937 cells was preceded by downregulation of transcript levels of C-MYC, increase of C-FOS mRNA, and induction of accumulation of C-FMS mRNA. By sequential use of LIF and ara-C we also demonstrate that the basis of synergism of both agents does not involve mechanisms at the level of receptor ligation but that synergism may be initiated by complementary intracellular metabolic cascades.
Leukemia 1990 Sep
PMID:Synergistic effect of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D-arabinofuranosylcytosine (Ara-C) on proto-oncogene expression and induction of differentiation in human U 937 cells. 214 31

Using (a) somatic cell hybrids retaining partial chromosome 5 and (b) clinical samples from patients with acquired deletions of the long arm of chromosome 5, combined with chromosome 5-linked DNA probes, some of which exhibited RFLPs, we have determined the order of a series of genes on chromosome 5. The order established is 5pter----MLVI-2----cen----HEXB----DHFR----Pi227- --- cp12.6----(IL5,IL4)----IL3----GMCSF---- FGFA---- (CSF1R,PDGFR)----(treC,ADRBR)----(ARH-H9,CSF1 )----qter. The suggested order and orientation for the closely linked IL3/GMCSF gene pair is cen----5' IL3 3'----5' GMCSF 3'----qter, on the basis of analysis of the GMCSF rearrangement in HL60 DNA. The map position of the GRL locus, which was consistent with both somatic cell hybrid and 5q- analyses, was telomeric to GMCSF and centromeric to CSF1R/PDGFR, near FGFA. Long-range restriction-enzyme analysis of 5q- DNAs did not detect rearrangements of 5q-linked probes except in HL60 DNA, but it did reveal putative long-range RFLPs of several loci. RFLPs for GRL, Pi227, cp12.6, IL3, and CSF1R can detect deletions in bone marrow and in leukemia cells from patients with acquired 5q deletions.
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PMID:Order of genes on human chromosome 5q with respect to 5q interstitial deletions. 229 53

Growth and maturation of B lymphocytes from stem cells require a series of complex processes that are dependent at least in part on growth factors. Uncontrolled expression of receptors from these early growth factors may contribute to a leukaemogenesis of such early B cell progenitors. We show here that early pre-pre-B cells, but not mature B cells, express the PDGF receptor-beta (PDGFR-beta). These receptors contain a protein tyrosine kinase domain which is activated upon ligation with PDGF in pre-pre-B cells. Further, pre-pre-B leukaemia cells seem to express more PDGFR-beta compared with their normal counterparts, suggesting a role for these receptors in growth promotion of leukaemia cells.
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PMID:Functional platelet-derived growth factor-beta (PDGF-beta) receptor expressed on early B-lineage precursor cells. 758

In a significant proportion of patients with acute myeloid leukemia (AML), a series of hematological alterations--including refractory anemia, neutropenia, thrombocytopenia, abnormal iron metabolism, and elevated levels of blast cells both in peripheral blood and bone marrow--are observed before the diagnosis of AML is made. This preleukemic state has called the attention of several investigators around the world, since it represents a way to study the origin and progression of leukemia in man. During the past 5 years, major advances in the molecular and cellular biology of this disease have been achieved. It is now known that preleukemia is a clonal disorder that arises from a malignant transformation at the level of primitive pluripotent hemopoietic stem cells. The hemopoietic progenitors in preleukemic patients have abnormal responses to hemopoietic regulators, thus, they do not seem to follow the controlled proliferation observed in the hemopoietic system under normal conditions. The mechanisms of cell differentiation and maturation are also altered, leading to the production of immature (blast) cells, instead of the development of fully mature erythrocytes, granulocytes, platelets and lymphocytes. Several oncogenes, such as C-FMS and RAS, have been found to be structurally altered in a significant proportion of preleukemic patients, suggesting that they may be involved in the pathogenesis of the disease. In spite of the advances made during the last few years, major questions regarding the biology of this hematological disorder are still unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human preleukemia: cellular, molecular and clinical aspects. 811 54

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

Aberrant expression of FLT3 has been found in most cases of B-lineage ALL and AML, and subsets of T cell ALL, CML in blast crisis and CLL. In 20% of patients with AML the receptor has small internal tandem duplications of the juxtamembrane region which appear to contitutively activate the receptor. To investigate whether FLT3 activation could play a role in leukemia, we generated a constitutively activated FLT3 by fusing its cytoplasmic domain to the helix-loop-helix domain of TEL in analogy to the fusion that occurs with TEL-PDGFR in CMML. In vitro translation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric receptor. Constitutively activated TEL-FLT3 conferred IL-3 independence and long-term proliferation to transfected Ba/F3 cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL-FLT3 expressing Ba/F3 cells in the absence of IL-3. These data suggest a possible role for the JAK/STAT pathway in FLT3 signaling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into syngeneic mice caused mortality in all mice by 3 weeks after injection. Histopathologic analysis demonstrated a massive infiltration of mononuclear cells in the liver, spleen and bone marrow. The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.
Leukemia 2000 Oct
PMID:Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. 1102 52

SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.
Leukemia 2003 Feb
PMID:Effect of imatinib on haematopoietic recovery following idarubicin exposure. 1496 Oct 27

Myeloid leukaemias are frequently associated with translocations and mutations of tyrosine kinase genes. The products of these oncogenes, including BCR-ABL, TEL-PDGFR, Flt3 and c-Kit, have elevated tyrosine kinase activity and transform haematopoietic cells, mainly by augmentation of proliferation and enhanced viability. Activated ABL kinases are associated with chronic myeloid leukaemia. Mutations in platelet-derived growth factor receptor beta are associated with chronic myelomonocytic leukaemia. Flt3 or c-Kit cooperate with other types of oncogenes to create fully transformed acute leukaemias. Elevated activity of these tyrosine kinases is crucial for transformation, thus making the kinase domain an ideal target for therapeutic intervention. Tyrosine kinase inhibitors for various kinases are currently being evaluated in clinical trials and are potentially useful therapeutic agents in myeloid leukaemias. Here, the authors review the signalling activities, mechanism of transformation and therapeutic targeting of several tyrosine kinase oncogenes important in myeloid leukaemias.
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PMID:Targeting mutated tyrosine kinases in the therapy of myeloid leukaemias. 1516 29

PDGF and its receptors are involved in a variety of diseases: cancers, atherosclerosis, balloon injury induced restenosis, pulmonary fibrosis and more. In all cases enhanced signaling of the receptor is the hallmark. In some cases, like chronic monomyelocytic leukemia (CMML), the persistent PDGFR signaling is essential for the survival of the cancer cell. These findings induced the research community as well as the pharmaceutical industry to develop agents that block PDGFR signaling. The possible utilization of PDGFR kinase inhibitors as anti-restenosis agents is likely to move ahead of the utilization of these agents to treat human malignancies.
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PMID:PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. 1520 14

Eosinophilia sometimes occurs in acute myeloid leukemia (AML), especially in core binding factor (CBF) leukemia. However, the pathogenesis of the differentiation from leukemic progenitors to eosinophils is not well understood in this type of leukemia. Recent reports showed that a novel fusion tyrosine kinase, Fip1-like1 (FIP1L1) platelet-derived growth factor receptor alpha (PDGFRalpha), is found in idiopathic hypereosinophilic syndrome. The involvement of another chimeric gene, PDGFRbeta, was also reported in myeloproliferative disorder with eosinophilia. These chimeric genes cause constitutive activation of PDGFR tyrosine kinases. On the other hand, a two-hit model for the pathogenesis of AML, which seems to be caused by inactivating mutations in transcription factors and genetic lesions in tyrosine kinase resulting in constitutive activation, has been proposed. On the basis of these findings, we screened for the expression of the FIP1L1-PDGFRalpha fusion gene and for mutations in the juxtamembrane and tyrosine kinase domains of PDGFRalpha/beta genes in 22 cases of CBF leukemia with eosinophilia. Among these cases, no FIP1L1-PDGFRalpha fusion gene was found. Although cDNA sequencing also detected three types of single-nucleotide alterations at kinase domains in PDGFRalpha/beta genes, all of them were silent changes and polymorphisms. Therefore, PDGFRalpha/beta genes do not appear to play a significant pathogenetic role in eosinophilia or leukemogenesis of CBF leukemia.
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PMID:Molecular analysis of PDGFRalpha/beta genes in core binding factor leukemia with eosinophilia. 1634 67


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