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)

Three of the ets oncogene superfamily members v-ets, Spi-1/PU.1 and Fli-1, have been shown to be directly involved in retroviral-mediated acute erythroleukemias. The Fli-1 gene was found to be rearranged in 75% of the erythroleukemias induced by Friend murine leukemia virus (F-MuLV), suggesting that it could play a key role in cellular transformation. We have previously isolated and characterized the human Fli-1 gene and have found it to be highly homologous (80%) to the human erg-2 gene. Human Fli-1 was also shown to be rearranged in Ewing's sarcoma cases, in which the amino-terminal region of the Fli-1 gene was replaced with a novel coding region of a putative RNA-binding protein, EWS. In this report, we show that the recombinant Fli-1 protein expressed in bacteria binds to DNA in a sequence-specific manner. It appears that Fli-1 and erg proteins fall into the category of ets proteins that recognize limited ets target sequences, unlike c-ets-1, ets-2 and Elk-1. The Fli-1 gene was found to activate the transcription of the reporter gene that was linked to Fli-1 target sequences, suggesting that Fli-1 is a sequence-specific transcriptional activator. Deletion analysis revealed the presence of two autonomous transcriptional activation domains, one at the amino-terminal region (amino-terminal transcriptional activation domain, ATA) and the other at the carboxy-terminal region (carboxy-terminal transcriptional activation domain, CTA). Secondary structural analysis of ATA and CTA domains revealed the presence of helix-loop-helix (H-L-H) and/or turn-loop-turn (T-L-T) regions. From these results it appears that a portion of the Fli-1 ATA domain (H-L-H region) was replaced by the amino-terminal domain of EWS gene in Ewing's sarcoma cases. Therefore alteration in the transcriptional activation function of Fli-1 may be responsible for human malignancies such as sarcomas, leukemias and lymphomas in which this gene is rearranged.
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PMID:Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein. 833 42

The ELM erythroleukemia is novel in that long-term survival of leukemic cells in culture (ELM-D cells) is dependent on contact with a bone marrow-derived stromal feeder cell layer. However, a number of stroma-independent (ELM-I) mutants that vary in their ability to differentiate in vitro in response to erythropoietin and interleukin-3 have been derived. We have attempted to define the genetic changes responsible for these different phenotypes. At the p53 locus in the primary leukemic cells, one copy of the gene has been lost whereas the other contains an 18-bp depletion, implicating its mutation as an early step in the development of the leukemia. Changes in ets gene expression have also been found. The Fli-1 gene region is rearranged in the primary tumor because of the insertion of a retrovirus inserted upstream of one Fli-1 allele, but this does not result in Fli-1 gene activation in any of the ELM-D or ELM-I cell lines except one. It seems significant that this line is the only one to have lost the ability to differentiate in response to erythropoietin. In addition, up-regulation of erg is associated with stromal cell-independent growth, since all ELM-I mutants have moderate levels of erg mRNA, whereas only low or undetectable levels are found in primary leukemic cells in vivo or in ELM-D cells in vitro. This up-regulation of erg mRNA seems to be important for stromal cell-independent growth, since ELM-D cells show elevated expression of the erg gene after separation from stromal cells. This seems to be made permanent in ELM-I mutants, since they do not down-regulate erg mRNA when grown in contact with stromal cells. We therefore propose that ets family members regulate both the survival and differentiation of erythroid cells.
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PMID:Differentiation arrest and stromal cell-independent growth of murine erythroleukemia cells are associated with elevated expression of ets-related genes but not with mutation of p53. 835 1

The erythroleukemias induced by Friend murine leukemia virus (F-MuLV) result from the accumulation of a number of genetic changes, including activation of the Fli-1 proto-oncogene and inactivation of the p53 tumor suppressor gene. We have determined the temporal order of mutation of the genes involved in this multistage malignancy, by serial in vivo transplantation of F-MuLV induced primary erythroleukemias into syngenic Balb/c mice. These primary tumors are capable of growing when transplanted into syngenic mice, but die after several days of in vitro culture. From the transplanted tumors grown in syngenic mice, erythropoietin-dependent cell lines were established in culture that are clonally related to cells in the primary tumors. We show that retroviral insertional activation of the Fli-1 ets family member is the first detectable genetic event in F-MuLV induced primary erythroleukemias. Mutations in the p53 gene were observed in the Epo-dependent cell lines but not in the transplanted erythroleukemias used to establish these cell lines in culture. These data suggest that activation of Fli-1 plays an important role in the early stages of F-MuLV-induced leukemia, perhaps by altering the self-renewal probabilities of erythroid progenitor cells and that p53 mutations immortalize these cells, enabling them to grow in vitro in the presence of Epo.
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PMID:Temporal order and functional analysis of mutations within the Fli-1 and p53 genes during the erythroleukemias induced by F-MuLV. 837 83

The Cas-Br-E murine leukemia virus is a non-defective retrovirus that induces non-T-, non-B-cell leukemias in susceptible NIH/Swiss mice. A collection of tumors was examined for genomic DNA structure and RNA expression of known or putative proto-oncogenes and one tumor-suppressor gene, with the aim of identifying genes involved in Cas-Br-E-induced non-T-, non-B-cell leukemogenesis. Fli-1, p53, and Evi-1 were found to be rearranged in 72%, 23%, and 18% of the tumors, respectively, whereas no DNA alteration were detected for c-myc, c-myb, Pim-1, Evi-2, and EpoR genes. Evi-1 rearrangements are rarely associated with p53 or Fli-1 alterations. However, rearrangements of these last two genes are very often associated within the same tumor. Moreover, patterns of coordinated expression of critical cell growth-regulating genes are consistently associated with specific tumor types. These data suggest that Cas-Br-E can induce two types of hematopoietic neoplasias by different mechanisms.
Leukemia 1993 Jul
PMID:Expression and DNA rearrangement of proto-oncogenes in Cas-Br-E-induced non-T-, non-B-cell leukemias. 839 16

The late stages of the erythroleukemias induced by either the replication-defective Friend spleen focus-forming virus (SFFV) or the Friend murine leukemia virus (F-MuLV) are associated with the insertional activation of one of two members (Spi-1 or Fli-1) of the Ets protooncogene family of transcriptional factors. Fli-1 is not rearranged or activated in the erythroleukemias induced by SFFV, and similarly Spi-1 is not rearranged or activated in the leukemic cell clones induced by F-MuLV. This strict specificity of integration sites suggests that Fli-1 and Spi-1 may be functionally distinct and transactivate different downstream genes during the progression of multistage Friend erythroleukemia. In this study, we show that the Fli-1 protein, like other Ets proteins, has DNA-binding activity and can act as a sequence-specific transcriptional activator. We also show that the Fli-1 and Spi-1 proteins are functionally distinct in that they recognize and transactivate through distinct DNA binding sites. Furthermore, we have identified an octanucleotide core sequence that is required in vitro for optimal binding of Fli-1 to the Drosophila E74 target and the promoter sequence of the human GPIIB gene.
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PMID:The Fli-1 proto-oncogene, involved in erythroleukemia and Ewing's sarcoma, encodes a transcriptional activator with DNA-binding specificities distinct from other Ets family members. 850 83

The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its activation by either chromosomal translocation or proviral insertion leads to Ewing's sarcoma in humans or erythroleukemia in mice, respectively, Fli-1 is preferentially expressed in hematopoietic and endothelial cells. This expression pattern resembled that of c-ets-1, another ets gene closely related and physically linked to Fli-1. We also generated a germ line mutation in Fli-1 by homologous recombination in embryonic stem cells. Homozygous mutant mice exhibit thymic hypocellularity which is not related to a defect in a specific subpopulation of thymocytes or to increased apoptosis, suggesting that Fli-1 is an important regulator of a prethymic T-cell progenitor. This phenotype was corrected by crossing the Fli-1 deficient mice expressing Fli-1 cDNA. Homozygous mutant mice remained susceptible to erythroleukemia induction by Friend murine leukemia virus, although the latency period was significantly increased. Surprisingly, the mutant Fli-1 allele was still a target for Friend murine leukemia virus integration, and leukemic spleens with a rearranged Fli-1 gene expressed a truncated Fli-1 protein that appears to arise from an internal translation initiation site and alternative splicing around the neo cassette used in the gene targeting. The fortuitous discovery of the mutant Fli-1 protein, revealed only as the result of the clonal expansion of leukemic cells harboring a rearranged Fli-1 gene, suggests caution in the interpretation of gene-targeting experiments that result in either no or only a subtle phenotypic alteration.
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PMID:Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia. 864 78

The human leukemia cell line K562 can be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) to differentiate along the megakaryocytic pathway, generating morphological changes and increased expression of lineage-specific surface markers. We report that TPA-treated K562 cells also express higher levels of FLI-1/ERGB, a member of the ETS family of transcription factors. Furthermore, introduction of a retroviral construct expressing human FLI-1/ERGB into K562 cells induces changes similar to those seen following TPA treatment, including increased adherence to the surface of the culture vessel and altered size and morphology. Infected cells exhibit higher levels of the megakaryocyte marker CD41a and, to a lesser extent, CD49b. These markers, as well as virally encoded FLI-1/ERGB-specific RNA and protein, are expressed at the highest levels in the attached cell population, while the growth rate of adherent cells is reduced, and the fraction of cells in G0-G1 is increased. FLI-1/ERGB virus-infected cells also exhibit increased expression of hemoglobin, a marker of erythroid differentiation. Our results suggest FLI-1/ERGB plays a role in controlling differentiation and gene expression along the megakaryocyte/platelet pathway, and further implicate ETS-related genes in the control of multiple developmentally regulated hematopoietic genes.
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PMID:Increased expression of the ETS-related transcription factor FLI-1/ERGB correlates with and can induce the megakaryocytic phenotype. 893 Apr 2

Retroviral insertional activation of the Fli-1 proto-oncogene is the first genetic event associated with the induction of erythroleukemias by the Friend murine leukemia virus (F-MuLV). Mutations within p53, which are only detected in cell lines established from transplanted tumors, have been previously shown to be associated with the immortalization of erythroleukemic cells in culture. In this study, we have demonstrated that primary erythroleukemic cells grown in liquid culture undergo rapid apoptosis independent of the stabilization of wild-type p53 protein. Further confirmation that the programmed cell death observed for liquid-cultured F-MuLV-induced primary erythroleukemic cells is largely p53 independent was provided by experimentation with a transgenic mouse line containing multiple copies of the dominant negative mutant p53Pro-193 allele. Erythroleukemic cells taken from tumor-bearing transgenic mice expressing high levels of the mutant p53Pro-193 undergo programmed cell death in culture in a manner that is largely identical to that observed for tumor cells derived from nontransgenic littermates. Furthermore, the rate of development of F-MuLV-induced erythroleukemias for both p53Pro-193-transgenic and nontransgenic littermates are similar. Moreover, cytogenetic analysis indicates that primary erythroleukemia cells are diploid, whereas chromosomal aberrations were observed in all established cell lines. These results are consistent with the notion that mutations within the p53 tumor suppressor gene affect genomic stability, subsequently leading to changes in gene expression that are associated with the immortalization of erythroid progenitor cells.
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PMID:p53-independent tumor growth and in vitro cell survival for F-MuLV-induced erythroleukemias. 895 33

The Fli-1 protein is a member of the ets proto-oncogene family, whose overexpression is a consequence of Friend murine leukemia virus (F-MuLV) integration in Friend erythroleukemic cells. We present evidence that Fli-1 and the retinoic acid receptor (RAR alpha) can reciprocally repress one another's transcriptional activation. Overexpression of Fli-1 inhibits the retinoic acid-induced activation of genes carrying a functional retinoic acid response element (RARE). Conversely, RAR alpha is able to repress Fli-1-mediated transcriptional activation. Transfection analysis of RAR alpha and Fli-1 mutants in cultured cells demonstrate that the DNA binding domain of RAR alpha and the N-terminal region of Fli-1 are required for repression. Gel retardation analysis demonstrates that RAR alpha cannot bind to the Fli-1 binding site in the E74 promoter and the expression of Fli-1 does not affect RAR alpha binding to DNA. Furthermore, the data suggest an indirect interaction between Fli-1 and RAR alpha mediated by a 'bridging' factor(s) present in nuclear extracts from RM10 erythroleukemia cells. Fli-1 also interferes with the action of receptors for thyroid or glucocorticoid hormone in several hematopoietic cell lines. The RA-induced differentiation and decrease of cell proliferation was blocked in myeloblastic leukemia HL-60 cells overexpressing the N-terminal region of Fli-1 at physiological concentrations of RA. These data suggest that accumulation of Fli-1 can oppose the transcriptional activity of hormone receptors in hematopoietic cells.
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PMID:Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1. 944 55

The proto-oncogene Fli-1, a member of Ets family is rearranged or activated through proviral integration in erythroleukemias, induced by Friends' Murine Leukemia Virus. The DNA binding domain (ETS domain) of Fli-1 is fused to the RNA binding domain of EWS by t(11q24:22q12) chromosomal translocation in Ewing's sarcoma and primitive neuroectodermal tumors. Screening of human cDNA libraries has identified two different 5'-termini and alternatively spliced forms of the human Fli-1 gene (Fli-1b), suggesting the possible existence of two independent promoters. The genomic sequence adjacent to the alternate exon of human Fli-1b gene shows functional promoter activity when cloned in promoter-less CAT expression vector and transfected into QT-6 cells. The transcription initiation (CAP) site and minimum promoter region necessary for function were localized. The 5'-flanking regions of human Fli-1b and mouse Fli-1 show 80% homology suggesting conserved promoter regulatory elements. The Fli-1b 5'-flanking sequence lacks canonical TATA or CCAAT boxes but contains a partially conserved TATA-like sequence at position 242. Several transcription factor binding sequences like ATF/CREB, E2A-PBX1, EBP, PEA-3, ETS-2, Sp-1, c-Myc, TBP, GATA-1 and Oct-3 were conserved in the promoter sequence. Functional promoter assays revealed that Fli-1b promoter shows very strong transcriptional activation compared to Fli-1 promoter. We also showed that variant Fli-1b has transcriptional activation properties similar to those of Fli-1. Fli-1b and Fli-1 show differential expression in various hematopoietic cell lines. This differential expression and promoter activities of Fli-1 and Fli-1b suggests that several mechanisms are involved in Fli-1 gene regulation which are mediated by many transcription factors.
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PMID:Fli-1b is generated by usage of differential splicing and alternative promoter. 976 25


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