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Sandra K Ruscetti - One of the best experts on this subject based on the ideXlab platform.
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retrovirus transformed Erythroleukemia cells induce central nervous system failure in a new syngeneic mouse model of meningeal leukemia
Leukemia Research, 2012Co-Authors: Gordon R Macpherson, Joan L Cmarik, Charlotte Hanson, Delores Thompson, Christine Perella, Sandra K RuscettiAbstract:Lack of suitable mouse models for central nervous system (CNS)-associated leukemias has hindered mechanism-guided development of therapeutics. By transplanting retrovirus-transformed mouse Erythroleukemia cells into syngeneic mice, we developed a new animal model of meningeal leukemia associated with rapid paralysis. Necropsy revealed massive proliferation of the leukemic cells in the bone marrow (BM) followed by pathological angiogenesis and invasion of the leukemic cells into the meninges of the CNS. Further analysis demonstrated that the Erythroleukemia cells secreted high levels of VEGF and preferentially adhered in vitro to fibronectin. This unique animal model for meningeal leukemia should facilitate studies of engraftment and proliferation of leukemic cells in the BM and their invasion of the CNS as well as pre-clinical evaluation of experimental therapeutics for CNS-associated leukemias.
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friend spleen focus forming virus activates the tyrosine kinase sf stk and the transcription factor pu 1 to cause a multi stage Erythroleukemia in mice
Viruses, 2010Co-Authors: Joan L Cmarik, Sandra K RuscettiAbstract:Hematological malignancies in humans typically involve two types of genetic changes: those that promote hematopoietic cell proliferation and survival (often the result of activation of tyrosine kinases) and those that impair hematopoietic cell differentiation (often the result of changes in transcription factors). The multi-stage Erythroleukemia induced in mice by Friend spleen focus-forming virus (SFFV) is an excellent animal model for studying the molecular basis for both of these changes. Significant progress has been made in understanding the molecular basis for the multi-stage Erythroleukemia induced by Friend SFFV. In the first stage of leukemia, the envelope protein encoded by SFFV interacts with and activates the erythropoietin (Epo) receptor and the receptor tyrosine kinase sf-Stk in erythroid cells, causing their Epo-independent proliferation, differentiation and survival. In the second stage, SFFV integration into the Sfpi1 locus activates the myeloid transcription factor PU.1, blocking erythroid cell differentiation, and in conjunction with the loss of p53 tumor suppressor activity, results in the outgrowth of malignant cells. In this review, we discuss the current level of understanding of how SFFV alters the growth and differentiation of erythroid cells and results in the development of Erythroleukemia. Our knowledge of how SFFV causes Erythroleukemia in mice may give us clues as to how the highly related human retrovirus XMRV causes malignancies in humans.
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dna hypomethylation caused by lsh deletion promotes Erythroleukemia development
Epigenetics, 2008Co-Authors: Tao Fan, Anja Schmidtmann, Victorino Briones, Heming Zhu, Hyung Chan Suh, John Gooya, Jonathan R Keller, Jean Roayaei, Miriam R Anver, Sandra K RuscettiAbstract:Hematopoietic malignancies are frequently associated with DNA hypomethylation but the molecular mechanisms involved in tumor formation remain poorly understood. Here we report that mice lacking Lsh develop leukemia associated with DNA hypomethylation and oncogene activation. Lsh is a member of the SNF2 chromatin remodeling family and is required for de novo methylation of genomic DNA. Mice that received Lsh deficient hematopoietic progenitors showed severe impairment of hematopoiesis, suggesting that Lsh is necessary for normal hematopoiesis. A subset of mice developed Erythroleukemia, a tumor that does not spontaneously occur in mice. Tumor tissues were CpG hypomethylated and showed a modest elevation of the transcription factor PU.1, an oncogene that is crucial for Friend virus induced Erythroleukemia. Analysis of Lsh-/-hematopoietic progenitors revealed widespread DNA hypomethylation at repetitive sequences and hypomethylation at specific retroviral elements within the PU.1 gene. Wild type cells showed...
Y Bendavid - One of the best experts on this subject based on the ideXlab platform.
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continuous fli 1 expression plays an essential role in the proliferation and survival of f mulv induced Erythroleukemia and human Erythroleukemia
Leukemia, 2009Co-Authors: J W Cui, L M Vecchiarellifederico, Guan Wang, Y BendavidAbstract:Erythroleukemia induced by Friend Murine Leukemia Virus (F-MuLV) serves as a powerful tool for the study of multistage carcinogenesis and hematological malignancies in mice. Fli-1, a proto-oncogene and member of the Ets family, is activated through viral integration in F-MuLV-induced Erythroleukemia, and is the most critical event in the induction of this disease. Fli-1 aberrant regulation is also observed in human malignancies, including Ewing's sarcoma, which is often linked to expression of the EWS/Fli-1 fusion oncoprotein. Here we examined the effects of Fli-1 inhibition to further elucidate its role in these pathological occurrences. The constitutive suppression of Fli-1, through RNA interference (RNAi), inhibits growth and induces death in F-MuLV-induced Erythroleukemia cells. Expression of a dominant negative protein Engrailed (En)/Fli-1 reduces proliferation of EWS/Fli-1-transformed NIH-3T3 cells, and both F-MuLV-induced and human Erythroleukemia cells. F-MuLV-induced Erythroleukemia cells also display increased apoptosis, associated with reduced expression of bcl-2, a known fli-1 target gene. Introduction of En/Fli-1 into an F-MuLV-infected erythroblastic cell line induces differentiation, as shown by increased α-globin expression. These results suggest, for the first time, an essential role for continuous Fli-1 overexpression in the maintenance and survival of the malignant phenotype in murine and human Erythroleukemias.
Lucio Cocco - One of the best experts on this subject based on the ideXlab platform.
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Nuclear but not Cytoplasmic Phospholipase C β1 Inhibits Differentiation of Erythroleukemia Cells
Cancer research, 1998Co-Authors: Alessandro Matteucci, Irene Faenza, Lucia Manzoli, Daniela Peruzzi, A Bavelloni, S G Rhee, Lucio CoccoAbstract:A body of evidence has shown the existence of a nuclear phosphoinositide cycle in different cell types. The cycle is endowed with kinases as well as phosphatases and phospholipase C (PLC). Among the PLC isozymes, the beta family is characterized by a long COOH-terminal tail that contains a cluster of lysine residues responsible for nuclear localization. Indeed, PLC beta 1 is the major isoform that has been detected in the nucleus of several cells. This isoform is activated by insulin-like growth factor I, and when this isoform is lacking, as a result of gene ablation, the onset of DNA synthesis induced by this hormone is abolished. On the contrary, PLC beta 1 is down-regulated during the erythroid differentiation of Friend Erythroleukemia cells. A key question is how PLC beta 1 signaling at the nucleus fits into the erythroid differentiation program of Friend Erythroleukemia cells, and whether PLC beta 1 signaling activity is directly responsible for the maintenance of the undifferentiated state of Erythroleukemia cells. Here we present evidence that nuclear PLC beta 1 but not the isoform located at the plasma membrane is directly involved in maintaining the undifferentiated state of Friend Erythroleukemia cells. Indeed, when wild-type PLC beta 1 is overexpressed in these cells, differentiation in response to DMSO is inhibited in that the expression of beta-globin is almost completely abolished, whereas when a mutant lacking the ability to localize to the nucleus is expressed, the cells differentiate, and the expression of beta-globin is the same as in wild-type cells.
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phosphoinositide signaling in nuclei of friend cells tiazofurin down regulates phospholipase c β1
Cancer Research, 1995Co-Authors: Lamberto Manzoli, A M Billi, R S Gilmour, Alberto M Martelli, Alessandro Matteucci, Silvia Rubbini, Lucio CoccoAbstract:Previous investigations have demonstrated the presence of conventional lipid kinases and phospholipase C (PLC) activities in nuclei of Friend Erythroleukemia cells. Moreover, when Friend Erythroleukemia cells are treated for 96 h with the antitumor drug tiazofurin, the induction of erythroid differentiation is accompanied by changes in amounts of both phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate due to the inhibition of an uncharacterized nuclear PLC activity. Here, we show that the nuclear PLC beta 1 isoform is down-regulated by tiazofurin (5 microM) treatment of Friend Erythroleukemia cells as shown by both Western blot and Northern blot analyses for PLC beta 1 message. This indicates that PLC beta 1 down-regulation is tightly linked with erythroid differentiation of Friend Erythroleukemia cells and that the autonomous nuclear signaling via inositol lipid cycle can be controlled by the antitumor drug tiazofurin.
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phosphoinositide signaling in nuclei of friend cells phospholipase c β down regulation is related to cell differentiation
Cancer Research, 1994Co-Authors: Alberto M Martelli, Lamberto Manzoli, A M Billi, R S Gilmour, Luca M Neri, Andrea Ognibene, Lucio CoccoAbstract:Abstract Previous investigations have demonstrated the existence of an autonomous intranuclear inositide cycle endowed with conventional lipid kinases and phospholipase C (PLC) which is the isoform β in Swiss 3T3 cells, PC12 pheochromocytoma cells, human osteosarcoma SaOS-2 cells, and rat liver. The presence of PLC has been investigated in nuclei of Friend Erythroleukemia cells. Both β and γ isoforms are present in these nuclei. When Friend cells undergo terminal erythroid differentiation in the presence of dimethyl sulfoxide the PLCβ isoform is down-regulated as shown by immunochemical and immunocytochemical analysis, by determination of enzymatic activity directly and in the presence of neutralizing monoclonal antibodies and also by Northern blot for PLC β message. By contrast, the amount of PLCγ and its activity are unaffected by erythroid differentiation. Thus, the presence of a nuclear PLCβ, the activity and expression of which are modulated during differentiation of Erythroleukemia cells, implicates a role for nuclear phosphoinositide signaling in the processes of cell determination and indicates the nuclear PLCβ as a key enzyme of the cycle in relation to the erythroid differentiative commitment of murine Erythroleukemia cells.
Yaacov Bendavid - One of the best experts on this subject based on the ideXlab platform.
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enhanced natural killer cell and erythropoietic activities in vegf a overexpressing mice delay f mulv induced Erythroleukemia
Blood, 2007Co-Authors: David Cervi, Yuval Shaked, Mehran Haeri, Tatiana Usenko, Christina R Lee, Jody J Haigh, Andras Nagy, Robert S Kerbel, Eitan Yefenof, Yaacov BendavidAbstract:We have previously reported that VEGF-A, in combination with MCP-5, contributes to leukemia progression within the splenic microenvironment of mice infected with F-MuLV. To study the influence of constitutively elevated VEGF-A levels on the progression of Erythroleukemia, mice heterozygous for a VEGF-A “hypermorphic” allele (Vegfhi/+) were inoculated with F-MuLV. Unexpectedly, a significant delay in Erythroleukemia was observed in Vegfhi/+ mice when compared with wild-type controls. These results suggested an altered physiologic response arising from elevated VEGF-A levels that decelerated erythroleukemic progression. Characterization of hematopoiesis in Vegfhi/+ spleens showed a higher natural killer cell activity, elevated B cells, and a decrease in T-cell number. Furthermore, higher erythroid progenitors (ie, CD34+, CD36+, and Ter119+ cells) were evident in the bone marrow, spleen, and peripheral blood of Vegfhi/+ mice. The CFU-E levels were significantly elevated in Vegfhi/+ bone marrow cultures, and this elevation was blocked by a neutralizing antibody to VEGF-A receptor (VEGFR-2). Moreover, erythroleukemic mice were treated with recombinant erythropoietin and, similar to diseased Vegfhi/+ mice, showed a delay in disease progression. We propose that a compensatory erythropoietic response combined with increased natural killer (NK) cell activity account for the extended survival of erythroleukemic, Vegfhi/+ mice.
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friend virus induced Erythroleukemias a unique and well defined mouse model for the development of leukemia
Anticancer Research, 2003Co-Authors: David Cervi, Aloke Sarkar, Amandine H L Truong, You Jun Li, Yaacov BendavidAbstract:Retroviruses lacking oncogenes have been known to induce various types of cancer when inoculated into animals. Among these Friend virus, discovered by Charlotte Friend in 1957, is capable of inducing Erythroleukemias when injected into susceptible strains of mice. Since its discovery this murine model of leukemogenesis has been extensively used to study the multistage nature of cancer. In the past two decades, several oncogenes and tumour suppressor genes, which play critical roles in the induction and progression of Friend Erythroleukemia, have been identified. Retroviral insertional activation of Fli-1 and Spi-1/PU.1, as well as loss of tumour suppressor genes such as p53 or p45 NFE2 have been shown to he critical for the induction and progression of Friend virus-induced Erythroleukemias. The majority of these genetic changes have also been implicated in various types of human neoplastic transformations. In this review we will discuss the genetic changes associated with Friend Disease, the temporal order during induction and progression of disease, and the function of these genes in both normal erythroid development as well as malignant transformation.
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retroviral insertions downstream of the heterogeneous nuclear ribonucleoprotein a1 gene in Erythroleukemia cells evidence that a1 is not essential for cell growth
Molecular and Cellular Biology, 1992Co-Authors: Yaacov Bendavid, Maria Rosa Bani, Benoit Chabot, A De Koven, A BernsteinAbstract:A large number of novel cellular proto-oncogenes have been identified and cloned by analysis of common integration sites in retrovirally induced malignancies. In the multistage Erythroleukemias induced by the various strains of Friend leukemia virus, the analysis of proviral-integration events has led to the identification of two genes, Fli-1 and Spi-1, both novel members of the ets oncogene family of transcription factors. In this report, we describe the identification of another integration site, designated Fli-2 (Friend leukemia virus integration-2), in an Erythroleukemia cell line induced by Friend murine leukemia virus (F-MuLV). Rearrangements at the Fli-2 locus were found in two Erythroleukemia cell lines independently induced by F-MuLV and one leukemic cell line derived from the spleen of a mouse infected with the polycythemia strain of Friend leukemia virus. The deduced amino acid sequence of a cDNA corresponding to a transcript originating from genomic DNA adjacent to Fli-2 is identical to that of the human heterogeneous nuclear ribonucleoprotein A1 gene, a member of the gene family of RNA-binding proteins involved in RNA splicing. In one Erythroleukemia cell line, A1 expression was undetectable as a result of F-MuLV integration in one allele and loss of the other allele. These results suggest that perturbations in RNA splicing mechanisms may contribute to malignant transformation and provide direct evidence that the A1 protein is not required for cell growth.
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Erythroleukemia induction by friend murine leukemia virus insertional activation of a new member of the ets gene family fli 1 closely linked to c ets 1
Genes & Development, 1991Co-Authors: Yaacov Bendavid, Elizabeth B Giddens, K Letwin, Alan BernsteinAbstract:The retroviral integration site Fli-1 is rearranged in 75% of the Erythroleukemia cell clones induced by Friend murine leukemia virus (F-MuLV), whereas Spi-I/PU.1, a member of the ets family of DNA-binding proteins, is rearranged in 95% of the Erythroleukemias induced by Friend spleen focus-forming virus (SFFV). To determine the transcriptional domain defined by Fli-1, we have isolated a cDNA clone that is highly expressed only in Erythroleukemia cell lines with Fli-1 rearrangements. The protein sequence of this cDNA is very similar to Erg2, another member of the ets gene family. The hydrophilic carboxy-terminal end of the Fli-1 cDNA shares significant sequence similarity to the DNA-binding ETS domain found in all members of the ets family. PFGE analysis localized Fli-1 within 240 kb of the ets-1 proto-oncogene on mouse chromosome 9 and human chromosome 11q23, suggesting that ets-1 and Fli-1 arose from a common ancestral gene by gene duplication. The involvement of the murine Fli-1, Spi-1, and avian v-ets genes in Erythroleukemia induction suggests that activation of ets gene family members plays an important role in the progression of these multistage malignancies.
Laurent Gouya - One of the best experts on this subject based on the ideXlab platform.
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TSPO2 translocates 5‐aminolevulinic acid into human Erythroleukemia cells
Biology of the Cell, 2020Co-Authors: Hana Manceau, Sophie Lefevre, Arienne Mirmiran, Claude Hattab, Hugo Sugier, Caroline Schmitt, Katell Peoc'h, Herve Puy, Mariano Ostuni, Laurent GouyaAbstract:Background: 5-aminolevulinic acid (ALA) is the first precursor of heme biosynthesis pathway. The exogenous addition of ALA to cells leads to protoporphyrin IX (PPIX) accumulation that has been exploited in photodynamic diagnostic and photodynamic therapy. Several types of ALA transporters have been described depending on the cell type, but there was no clear entry pathway for erythroid cells. The 18 kDa translocator protein (TSPO) has been proposed to be involved in the transport of porphyrins and heme analogs. Results: ALA-induced PPIX accumulation in Erythroleukemia cells (UT-7, K562) was impaired by PK 11195, a competitive inhibitor of both transmembrane proteins TSPO (1 and 2). PK 11195 did not modify the activity of the enzymes of heme biosynthesis, suggesting that ALA entry at the plasma membrane was the limiting factor. In contrast, porphobilinogen (PBG)-induced PPIX accumulation was not affected by PK 11195, suggesting that plasma membrane TSPO2 is a selective transporter of ALA. Overexpression of TSPO2 at the plasma membrane of Erythroleukemia cells increased ALA-induced PPIX accumulation, confirming the role of TSPO2 in the import of ALA into the cells. Conclusions: ALA-induced PPIX accumulation in erythroid cells involves TSPO2 as a selective translocator through the plasma membrane. Significance: This is the first characterization of molecular mechanisms involving a new actor in ALA transport in ALA-induced PPIX accumulation in Erythroleukemia cells, which could be inhibited by specific drug ligands.