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

Friend virus induced erythroleukaemia can be conveniently divided into a first stage and a second stage. The first stage results from the mitogenic stimulation of EPO-R by gp55. In the second stage, multiple proviral integrations appear to result in further transformation of the SFFV infected erythroblast to a leukaemogenic state. The first stage results from EPO-R activation. After retroviral entry, mediated through an unknown receptor, and after cDNA synthesis and proviral integration, viral proteins are synthesized. Gp55 binds and activates EPO-R. A small but measurable amount of gp55-EPO-R complex is transported to the cell surface (Casadewall et al, 1991). In the presence of helper virus, the defective SFFV genome is packaged and released for subsequent rounds of infection. During the first stage, erythroblasts proliferate but are not tumorigenic. During the second stage of Friend disease, subsequent infections result in further proviral integrations in the host genome. Some of these integrations result in increased Spi-1 expression, whereas others result in decreased p53 expression. These events appear to account for the leukaemogenic properties of cells at this stage, 4-6 weeks after the initial SFFV infection. The interaction between EPO-R and gp55 persists at this later stage, although its contribution to the malignant phenotype of the MEL cells is not known. The sequence of events during stage 1 and stage 2 does not appear to have absolute requirements. Starting with IL-3 dependent immortalized Ba/F3 cells, which already have some unknown proliferative mutation (Mathey-Prevot et al, 1986), gp55 and EPO-R can subsequently be introduced, resulting in tumorigenicity (Li et al, 1990). The primary focus of this review has been the early mitogenic stage of Friend disease. Several concepts have emerged regarding the interaction between gp55 and EPO-R. The interaction between the polypeptides is highly specific, occurs in the extracytoplasmic regions and the transmembrane region of the polypeptides and occurs within the same cell, not via cell-cell contact. Both EPO and gp55 activate EPO-R, via different binding sites, resulting in increased cellular tyrosine kinase activity. The first stage of Friend disease is an example of how a non-oncogene bearing retrovirus can induce leukaemia. The env gene of the SFFV is not a classical oncogene. It does not appear to be derived from a normal cellular proto-oncogene. The interaction of gp55 and EPO-R therefore supports the "receptor mediated leukaemogenesis" hypothesis (McGrath and Weissman, 1978, 1979).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The interaction of the erythropoietin receptor and gp55. 145 Nov 11

The development of Friend virus induced murine erythroleukaemia is associated with specific genetic events. One of these events is loss of wild type p53 expression, which can occur by internal deletion or proviral insertion in the p53 gene and by single point mutations in the coding sequence. In all cases, the corresponding wild type allele is absent. The high frequency of observed p53 mutations strongly suggests that inactivation of p53 may be an obligatory step in the development of Friend disease. Further evidence that abrogation of normal p53 expression contributes to the development of malignant clones was provided by in vitro reconstitution experiments in Friend cell lines: whereas exogenous mutant p53 was stably expressed in p53 negative FCLs, long term wild type p53 expression was not detected. Friend erythroleukaemia arises as a late consequence of infection of susceptible mice with Friend virus. In addition to p53 gene mutations, proviral insertions occur frequently adjacent to one of two cellular genes, Spi-1/PU.1 or Fli-1. Aberrant expression of these genes may therefore be involved in virus induced erythroleukaemia. Interaction of SFFV env gp55 with the EPO-R also appears to be important in providing a mitogenic signal to infected cells. The order in which these events occur and whether the order is relevant to the progression of the disease are not known. Investigation of the stepwise appearance of these events could provide information on the possible interactions of the gene products involved. Abrogation of normal p53 expression is not restricted to Friend erythroleukaemia: the observation of p53 mutations and allele loss in human breast, lung, colon and hepatocellular carcinomas and in leukaemia suggests that mutation of p53 may be the most common genetic abnormality detected in human cancer (reviewed in this issue). Studies of p53 expression in FCLs provided an early indication that p53 was a tumour suppressor gene. Further studies of the mechanisms by which wild type and mutant p53 affect the growth of p53 negative FCLs may reveal important biochemical properties of p53 in relation to cell cycle control and differentiation of erythroid cells.
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PMID:Friend virus induced murine erythroleukaemia: the p53 locus. 163 45

If the env gene of spleen focus-forming virus (SFFV) is replaced by a cDNA encoding a constitutively active form of the erythropoietin receptor, EPO-R(R129C), the resultant recombinant virus, SFFVcEPO-R, induces transient thrombocytosis and erythrocytosis in infected mice. Clonogenic progenitor cell assays of cells from the bone marrow and spleens of these infected mice suggest that EPO-R(R129C) can stimulate proliferation of committed megakaryocytic and erythroid progenitors as well as nonerythroid multipotent progenitors. From the spleens of SFFVcEPO-R-infected mice, eight multiphenotypic immortal cell lines were isolated and characterized. These included primitive erythroid, lymphoid, and monocytic cells. Some expressed proteins characteristic of more than one lineage. All cell lines resulting from SFFVcEPO-R infection contained a mutant form of the p53 gene. However, in contrast to infection by SFFV, activation of PU.1 gene expression, by retroviral integration, was not observed. One cell line had integrated a provirus upstream of the fli-1 gene, in a location typically seen in erythroleukemic cells generated by Friend murine leukemia virus infection. This event led to increased expression of fli-1 in this cell line. Thus, infection by SFFVcEPO-R can induce proliferation and lead to transformation of nonerythroid as well as very immature erythroid progenitor cells. The sites of proviral integration in clonal cell lines are distinct from those in SFFV-derived lines.
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PMID:A constitutively activated erythropoietin receptor stimulates proliferation and contributes to transformation of multipotent, committed nonerythroid and erythroid progenitor cells. 813 32

Erythropoietin (EPO) is the major regulator of mammalian erythropoisis, which stimulates the growth and differentiation of hematopoietic cells through interaction with its receptor (EPO-R). Here we use HEL cells (a human erythro-leukemia cell line) as a model to elucidate the pathway of signal transduction in the EPO-induced HEL cells. Our data show that the EPOR (EPO receptor) on the surface of HEL cells interacts with the Janus tyrosine protein kinase (Jak2) to transduce intracellular signals through phosphorylation of cytoplasmic proteins in EPO-treated HEL cells. Both STAT1 and STAT5 in this cell line are tyrosine-phosphorylated and translocated to nucleus following the binding of EPO to HEL cells. Furthermore, the binding of both STAT1 and STAT5 proteins to specific DNA elements (SIE and PIE elements) is revealed in an EPO-dependent manner. Our data demonstrate that the pathway of signal transduction following the binding of EPO to HEL cells is similar to immature erythroid cell from the spleen of mice infected with anemia strain of Friend virus.
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PMID:STAT1 is involved in signal transduction in the EPO induced HEL cells. 966 26

Expression of erythropoietin (EPO) receptor (EPO-R) was analysed in leukaemia cells from 150 patients with acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL). EPO-R was expressed in 81 (60%) out of 136 AML, and in vitro treatment with EPO led to proliferation of leukaemia cells in 13 (16%) out of 81 AML examined. EPO-R expression and in vitro response to EPO were observed in all subtypes of AML according to the French-American-British (FAB) classification. All eight patients with FAB-M6 expressed EPO-R, and one out of four showed an in vitro response to EPO. Although there was no significant correlation (r = 0.2522) between the amount of EPO-R and the in vitro response to EPO, all of the AML patients who showed in vitro response expressed EPO-R. Stem cell factor significantly enhanced both EPO-R expression and in vitro response to EPO. Interleukin-3 tended to increase in vitro response to EPO. CD phenotypes, the amount of granulocyte colony-stimulating factor (G-CSF) receptors and the amount of TPO receptors had no significant relationship with the amount of EPO-R. Patients with both EPO-R expression and in vitro response to EPO had shorter duration of complete remission than those without EPO-R (P = 0.0053). EPO-R was expressed in four (29%) out of 14 ALL, and none out of five ALL showed in vitro response to EPO.
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PMID:Quantitative expression of erythropoietin receptor (EPO-R) on acute leukaemia cells: relationships between the amount of EPO-R and CD phenotypes, in vitro proliferative response, the amount of other cytokine receptors and clinical prognosis. Japan Adult Leukaemia Study Group. 1065 24

Several years ago, we cloned and characterized from a B cell leukemia a new secreted protein which, on the basis of its high degree of structural homology with follistatin, was defined as a member of the follistatin family and accordingly named follistatin-related gene (FLRG). However, follistatin and FLRG revealed non-overlapping patterns of expression in various tissues thereby indicating the existence of non-redundant functional roles for these proteins throughout the organism. As known for a long time, follistatin is a biological regulator of activin and bone morphogenetic protein (BMP) function in various cellular systems: in particular, it inhibits the effects of activin on hematopoiesis. We therefore investigated the expression and effects of FLRG during human hematopoiesis with particular focus on the effect of this soluble glycoprotein in the regulation of erythropoiesis. For this purpose, we have for the first time, compared the role of Activin A, BMP2 and BMP4 during erythropoiesis, in primary human cells. Our results indicate that, BMP2 acts on early erythroid cells while Activin A acts on a more differentiated population. We report the induction by Activin A and BMP2 of cell commitment towards erythropoiesis in the absence of EPO. This induction involves two key events: increase of EPO-R and the decrease of GATA2 expression. Our results indicate that despite their high structural homology, follistatin and FLRG do not regulate the same signaling targets, therefore highlighting distinct functions and mechanisms for these two proteins in the human hematopoietic system. We thus propose a working model for the regulation of activin or BMP-induced human erythropoiesis by follistatin/FLRG.
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PMID:FLRG, member of the follistatin family, a new player in hematopoiesis. 1545 75

Human leukemias are considered clonal hematological malignancies initiated by chromosomal aberrations or epigenetic alterations occurring at the level of either pluripotent hematopoietic stem cells (HSCs) or early multipotent progenitors (MPPs). Leukemic cells are transformed, immortalized, actively proliferating cells that are still able to differentiate into cells resembling mature blood cells. Future therapies of leukemias require identification of molecular targets involved in hematopoiesis under normal and leukemic conditions and detailed understanding of the interactions between normal hematopoietic and leukemic cells within the bone marrow micro-environment. This review presents the basic aspects of hematopoiesis and highlights multilevel exploitable targets for leukemia therapy. These include HSC niche components, signaling pathways (SCF/c-kit-R, EPO-R-JAK2/STAT, Wnt, Notch, HOX), inducer-receptor interactions, superfine chromatin structure modifications, fused transcription factors, microRNAs and signaling of cell death through the Bcl-2 apoptotic switch (BH3-only proteins). The classes of therapeutics developed or being under development to eradicate human leukemias include novel antimetabolites, DNA hypomethylating agents, histone deacetylation inhibitors (HDACIs), retinoids and other inducers of differentiation, targeted monoclonal antibodies raised against cell surface proteins, pro-apoptotic receptor agonists (PARAs), BH3 peptidomimetics, cell cycle inhibitors, siRNAs and perhaps microRNAs. Some of these agents induce terminal differentiation while others promote cell cycle arrest and apoptosis in leukemia cells. At last but not least, this article describes the mechanisms of removal of damaged/harmful cells from organs since impairment in clearance of such cells can lead to autoimmune disorders by self-antigens.
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PMID:Multilevel targeting of hematopoietic stem cell self-renewal, differentiation and apoptosis for leukemia therapy. 1930 96