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)

Erythropoietin (Epo) autocrine stimulation has been implicated in erythroblastic leukemia. To examine whether this stimulation could occur intracellularly, we developed Epo autocrine models of stimulation in the human pluripotent UT-7 cell line. Retroviral expression of Epo totally abolished the growth factor requirement of UT-7 cells. Autonomous proliferation was not cell density-dependent and occurred at a unicellular level, showing a genuine autocrine mode of stimulation. Total blockage of Epo secretion induced by the endoplasmic reticulum-retention amino acids Lys-Asp-Glu-Leu (KDEL) signals in 11 lines prevented autonomous proliferation, whereas a leaky retention system, observed in 3 other lines, resulted in limited autocrine stimulation without true long-term autonomous proliferation. Production of Epo, in contrast to KDEL-modified Epo, induced reductions in Epo binding, Epo receptor (EpoR) mRNA, and phosphorylation levels similar to those induced by the addition of exogenous Epo to the parental cell line. In addition, autonomous growth and survival were inhibited by the addition of Epo-neutralizing antibodies, affording evidence that autocrine stimulation through EpoR activation takes place on the cell surface. Finally, phenotypic analysis of the virus-infected clones indicated that Epo production did not change the differentiative capacities of UT-7 cells. All these data show that Epo autocrine stimulation is dependent on Epo secretion and takes place on the cell surface. From all analyzed parameters, the effects of Epo autocrine stimulation and those of exogenously added Epo appear to be identical.
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PMID:Autocrine stimulation by erythropoietin (Epo) requires Epo secretion. 791 79

Cytokines are decisive for the regulation of the immune system as well as the renewal and maturation of the haematopoietic cells. The most important groups of substances, several of which are already produced by gentechnology, are the interferons, the interleukins and the haematopoietic growth factors. The main indications for the application of alpha-(less often beta-)Interferon in children are the juvenile larynx papillomatosis, chronic hepatitis B, viral encephalitis, and also chronic myeloic leukemia, extended haemangiomas, recurrent Langerhans cell histiocytosis and nasopharynx carcinomas. gamma-Interferon is administered successfully for chronic granulomatous disease and has recorded positive effects in therapy resistant rheumatoid arthritis, in kidney cell carcinoma and in osteopetrosis. G-CSF, GM-CSF and Interleukin 3 are the most effective haematopoietic growth factors currently in use. Through G-CSF congenital agranulocytosis (Kostmann syndrome) has become a treatable disease. Other proven applications are in the reduction of aplastic phases after chemotherapy and in critical situations of primary bone marrow failure as well as myelodysplastic syndromes, for prevention of transplant rejections after bone marrow transplantation and for mobilisation of stem cells into peripheral blood before apheresis. Erythropoietin is established in the treatment of chronic renal anaemia and is currently used in the treatment of anaemia in preterm infants. Finally, Interleukin 2 is also used for adoptive immunotherapy in children with minimal residual tumors. The future will show us, whether the spectrum of indications will expand and whether a definite benefit for sick children will result from a wider application of these substances. As long as the cost/benefit ratio for certain indications is not clear, the use of these drugs should be tested in prospective studies.
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PMID:[Clinical applications of cytokines in pediatrics]. 815 1

Erythropoietin (EPO) regulates proliferation and differentiation and prevents apoptosis of erythroid progenitor cells by binding to erythropoietin receptor (EPOR) expressed on the surface of those cells. The mechanism by which EPO signal is transmitted to the cells through EPOR is still unclear. In the present study, we introduced and expressed EPOR in an interleukin-3 (IL-3) dependent pro-B cell line, BAF-B03 and an interleukin-2 (IL-2)-dependent cytotoxic T cell line, CTLL-2 and analyzed their growth response to EPO and the DNA breakdown characteristic to apoptosis after deprivation of the growth factor. BAF-B03-derived cells expressing EPOR proliferated in response to EPO but CTLL-2-derived cells expressing EPOR (C/EPOR) did not. DNA from C/EPOR cells cultured in the absence of IL-2 with or without EPO had similar patterns of DNA breakdown. These results suggest that downstream signaling pathways for the cell proliferation and apoptosis-block are, at least, partially different between EPOR and IL-2 receptor (IL-2R).
Leukemia 1994 Apr
PMID:Erythropoietin receptor and interleukin-2 receptor use different downstream signaling pathways for proliferation and apoptosis-block. 815 74

Thrombopoietin (TPO) is a recently characterized growth and differentiation factor for megakaryocytes and platelets exerting its effects via the receptor MPL. We examined the expression of MPR on the cell surface of a panel of 43 myelomonocytic, erythroid and megakaryocytic leukemia cell lines and 21 primary acute myeloid leukemia (AML) cases by flow cytometry. With few exceptions MPL was found on all 32 erythroid/megakaryocytic cell lines and on all 11 growth factor-dependent myelomonocytic cell lines, albeit at variable percentages and intensities per cell population (with a 10% cut-off level for positivity still 30/43 cell lines scored as MPL positive). The majority of the primary AML samples (including all seven M6/M7 cases) expressed the MPL protein regardless of the morphological and immunological subtype (13/21 cases had >10% MPL-positive cells). Recombinant TPO overexpressed in hamster cells induced a mitogenic response in seven cell lines (one growth factor-independent and six factor-dependent lines) and in 3/21 AML specimens (two AML M2, one AML M7) as measured by 3H-thymidine incorporation. Expression of MPL clearly did not correlate with response to TPO. For further detailed studies of the interaction of TPO with other cytokines we used the AML M7-derived M-07e cells as an informative indicator cell line for which both murine and human TPO acted as a very potent mitogen in a dose-dependent fashion (3- to 11-fold proliferation increase relative to medium alone). This growth factor-dependent cell line which is normally cultured in conditioned medium containing several cytokines could be grown in long-term culture supplemented only with TPO. Co-incubation of M-07e with various cytokines and TPO showed additive proliferative effects for interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and synergistic responses for stem cell factor (SCF), interferon (IFN)-alpha, and to a lesser extent for IFN-gamma and tumor necrosis factor (TNF)-alpha. Erythropoietin (EPO), IL-1, IL-6, IL-11 and leukemia inhibitory factor (LIF), know as megakaryocytic maturation-inducing molecules, were not substantially effective, neither singly nor in combination with TPO, with regard to cell growth. Transforming growth factor (TGF)-beta1 antagonized the inductive effect of TPO on M-07e cell growth. Addition of TPO to cultures of megakaryocytic cell lines failed to significantly alter the ploidy distribution and the differentiation marker immunoprofile of the cells indicating a lack of maturation-inducing effects in this model system. In summary, TPO represents an efficient in vitro potentiator of megakaryocytic leukemia proliferation of at least some primary cases or cell lines. While TPO seems to be the major physiological regulator of megakaryocytopoiesis, the present data suggest also some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic leukemia cells as well, thus assigning to TPO a possible pathobiological role in leukemogenesis which would be of clinical relevance. Our data show that the response to TPO is not restricted to cells committed to the megakaryocytic differentiation pathway as we could demonstrate TPO-responsive megakaryocytic and non-megakaryocytic cell lines; thus, these cell lines represent powerful tools in such analyses. Consequently, this new cytokine needs to be properly examined so we can get a clear understanding of the clinical possibilities and dangers.
Leukemia 1996 Feb
PMID:Expression of the receptor MPL and proliferative effects of its ligand thrombopoietin on human leukemia cells. 863 39

Erythropoietin can be successfully used in the treatment of anaemia induced by chemotherapy and radiotherapy as well as for the treatment of anaemia induced by malignant disease without previous chemotherapy of radiotherapy. Erythropoietin administered during chemotherapy is effective in 50-70% patients, it has a more marked effect as a supplement to chemotherapy with cisplatinum and carboplatinum than non-platinum regimens. Erythropoietin reduces the consumption of red cell concentrates during chemotherapy on average by one half. Long-term administration of erythropoietin in anaemia caused by malignant disease alone proves most effective in multiple myeloma and in chronic lymphatic leukaemia or in non-Hodgkin lymphomas with a low malignity. The therapeutic responses defined as independence on transfusions and a rise of the haemoglobin level by at least 20 g/l, as compared with the pretreatment value, can be achieved in 60 to 80% of the patients. Erythropoietin is much less effective (10-20% therapeutic responses) in myelodysplastic syndrome, in myeloproliferative diseases or in aplastic anaemia. The authors give an account on the effectiveness of erythropoietin in different indications.
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PMID:[Erythropoietin in oncology. II. Evaluation of the effectiveness of erythropoietin in hematologic and oncologic diseases]. 876 96

Growth factors or humoral agents can support haemopoiesis in various bone marrow disorders. They have the ability to act on multiple cell lineages and in myeloid cells, and the potential to act on the neoplastic equivalent of normal cells. Anaemia is a common feature of multiple myeloma seen in at least two-thirds of patients at presentation. Erythropoietin is increasingly being used with variable effect for the treatment of this anaemia, especially in cases associated with renal failure and in patients in whom blood transfusion may be undesirable or contraindicated. We describe a patient treated with recombinant erythropoietin who developed fulminating malignant transformation. The demonstration of erythropoietin receptors on a human myeloma cell line and the occurrence of the rare complication of plasma cell leukaemia in our patient stresses the need for caution and invites detailed clinical and laboratory studies before its general use.
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PMID:Does erythropoietin accelerate malignant transformation in multiple myeloma? 913 33

The BCR/ABL oncogene encodes an activated tyrosine kinase that causes human chronic myelogenous leukemia. The mechanism of transformation, however, is complex and not well understood. One of the important contributions of BCR to transformation is believed to be dimerization or oligomerization of ABL, thereby activating ABL tyrosine kinase activity. We reasoned that if ABL was dimerized through other mechanisms, activation of the tyrosine kinase activity should also result, and the activated kinase may also be transforming. Erythropoietin is known to activate its receptor by causing dimerization, and therefore a synthetic oncogene was created by linking the extracytoplasmic and transmembrane domains of the EPO receptor with c-ABL. This chimeric receptor was stably expressed in Ba/F3 cells and, in the absence of EPO, had no detectable biological effect on the cells. EPO, however, induced a rapid, dose-dependent activation of ABL tyrosine kinase activity and phosphorylation of several cellular proteins. The major target proteins have been identified, and are very similar to the known substrates of BCR/ABL, including Shc, CBL, CRKL, and several proteins in the cytoskeleton. EPO treatment also resulted in biological effects that were remarkably similar to those of BCR/ABL, including improved viability, altered integrin function, and a weak mitogenic signal. The biological effects were in part dose-dependent, in that low EPO concentrations enhanced viability but did not cause proliferation. At high EPO doses, kinase activation was maximal, and a mitogenic effect was also revealed. In nude mice, Ba/F3 cells expressing this chimeric receptor did not cause detectable disease without administration of pharmacologic doses of EPO. If EPO was given intraperitoneally 5 days a week, however, a dose-dependent lethal leukemia resulted. This ligand-regulatable oncogene mimics some of the biological effects of BCR/ABL, and analysis of ABL mutants in this system will be useful to dissect the signaling pathways that cause CML.
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PMID:A chimeric receptor/oncogene that can be regulated by a ligand in vitro and in vivo. 931 68

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

Biotechnology is a rapidly developing area of drug development which has great growth potential. Development of genetically engineered drugs is very expensive and as these products become available the impact on healthcare costs could be vast. The cost-benefit ratio of biotechnology products needs to be established, but few relevant pharmacoeconomic studies are available. Issues in pharmacoeconomic analysis of genetically engineered drugs can be exemplified by the data available for alteplase, epoetin and interferon alpha-2b. One study concluded that thrombolysis with streptokinase rather than alteplase would substantially reduce the percentage of total hospital costs that were not reimbursed. However, differences in efficacy were not accounted for. Based on the superior efficacy of alteplase, a more extensive pharmacoeconomic analysis found that alteplase was more cost-effective than streptokinase when the agents were combined with aggressive reocclusion management. However, this conclusion may be altered by the finding of a more recent study that streptokinase may be at least as effective as alteplase. Economic factors involved in epoetin treatment of anaemia associated with chronic renal disease have been studied thoroughly. However, cost-effectiveness or cost-benefit analysis was not attempted, and improvement in quality of life with epoetin therapy also needs to be considered, to facilitate cost-utility analysis. Compared with chlorambucil, the use of interferon alpha-2b for hairy cell leukaemia resulted in significant direct and indirect cost savings, in a retrospective cost-benefit analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacoeconomics of genetically engineered drugs. 1017 57

Erythropoietin (Epo) is a major regulator of erythropoiesis that alters the survival, proliferation, and differentiation of erythroid progenitor cells. The mechanism by which these events are regulated has not yet been determined. Using HB60, a newly established erythroblastic cell line, we show here that Epo-induced terminal erythroid differentiation is associated with a transient downregulation in the expression of the Ets-related transcription factor Fli-1. Constitutive expression of Fli-1 in HB60 cells, similar to retroviral insertional activation of Fli-1 observed in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia, blocks Epo-induced differentiation while promoting Epo-induced proliferation. These results suggest that Fli-1 modulates the response of erythroid cells to Epo. To understand the mechanism by which Fli-1 regulates erythropoiesis, we searched for downstream target genes whose expression is regulated by this transcription factor. Here we show that the retinoblastoma (Rb) gene, which was previously shown to be involved in the development of mature erythrocytes, contains a Fli-1 consensus binding site within its promoter. Fli-1 binds to this cryptic Ets consensus site within the Rb promoter and transcriptionally represses Rb expression. Both the expression level and the phosphorylation status of Rb are consistent with the response of HB60 cells to Epo-induced terminal differentiation. We suggest that the negative regulation of Rb by Fli-1 could be one of the critical determinants in erythroid progenitor cell differentiation that is specifically deregulated during F-MuLV-induced erythroleukemia.
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PMID:Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation. 1033 Jan 85


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