Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LC-FeLV is a myc-containing strain of feline leukemia virus (FeLV) which exhibits only partial transforming activity in vitro and in vivo. LC-FeLV infection in kittens may induce, but does not necessarily induce, thymic lymphosarcoma in viremic animals after a short latency. These observations suggest that infection with LC-FeLV is not sufficient to induce complete transformation and that another genetic event(s) is required. One possibility for such an event is that the integrating provirus acts as an insertional mutagen and thereby disrupts the structure or function of another proto-oncogene. Using a strategy of transposon tagging, this possibility was examined in eight feline T-cell lymphosarcomas, including four induced by experimental infection with LC-FeLV, three induced by natural infection with FeLV, and one FeLV-negative tumor. The analysis demonstrated one locus, termed flvi-2, to be structurally altered in six of the tumors examined, including three induced by LC-FeLV and three in which no activated myc oncogene is apparent. Inverse polymerase chain reaction was used to demonstrate the presence and transcriptional orientation of proviruses integrated at flvi-2 in five of these tumors. The flvi-2 locus does not hybridize to cloned probes representing 21 previously identified proto-oncogenes or common domains of retroviral integration. Thus, the data suggest that interruption of the flvi-2 locus cooperates with the myc oncogene in the induction of T-cell lymphomas by LC-FeLV; indeed, the observations indicate that the insertional mutagenesis of flvi-2 plays a role in T-cell lymphomagenesis even in the absence of feline v-myc.
 ...
PMID:Insertional mutagenesis of flvi-2 in tumors induced by infection with LC-FeLV, a myc-containing strain of feline leukemia virus. 131 7

Primary lymphoid tumor cells induced by wild type or recombinant Moloney murine leukemia viruses were inoculated intravenously into sublethally irradiated, syngeneic mice and compared for their ability to reestablish in the recipient thymus and spleen. Lymphoid tumors induced by one recombinant, M-MuLV(myc), containing the v-myc oncogene from the avian MC29 retrovirus consistently reestablished in the thymus and spleen of recipient mice. Since tumors in the recipient thymus and spleen could have arisen by infection of host cells, or could reflect an expansion of a minor subpopulation from the donor tumor, we verified the donor and clonal origin of these tumors by Southern blot analysis using a virus-specific probe. As few as 500 of these tumor cells could migrate to the thymus via the blood and flourish in that microenvironment. In contrast, the majority of tumors induced by wild type M-MuLV or two other M-MuLV recombinants not containing v-myc sequences, inefficiently reestablished in the thymus of recipient mice following i.v. inoculation, although splenic tumors developed. These tumors could, however, multiply within the recipient thymus when inoculated intrathymically. Thus, the inability of tumors induced by wild type M-MuLV or M-MuLV recombinants lacking v-myc to reestablish in the thymus following i.v. inoculation appears to reflect inefficient 'thymic homing' rather than the ability to grow in the thymic microenvironment. Collectively, our data suggest that the thymic homing ability of M-MuLV(myc)-induced tumor cells is related to the presence of v-myc sequences or to the cell type transformed by M-MuLV(myc). Thus, we suggest that these cells may provide a useful model for studying how blood-borne metastatic cells, and possibly normal lymphocytes, enter the thymus by way of the microvasculature.
 ...
PMID:Induction of thymus-reestablishing lymphoid tumors by a murine leukemia virus carrying the avian v-myc oncogene. 132 92

Avian carcinoma retrovirus MH2 induces leukemia and solid tumors in chickens and transforms fibroblasts and macrophages in vitro. The genome of MH2 consists of two oncogenes, v-mht/mil and v-myc. Most of the transforming activity of MH2 is attributed to the v-myc oncogene. In contrast, the v-mht/mil oncogene alone does not induce a fully transformed phenotype of avian primary fibroblasts in vitro. It was shown previously that v-mht/mil is the avian homology of the v-raf oncogene in murine sarcoma retrovirus 3611. Because the v-raf oncogene transforms murine fibroblasts very efficiently, the present study tested the hypothesis that an extra segment in the 5' end of v-mht/mil relative to v-raf suppressed the fibroblast-transforming activity of v-mht/mil. By introducing an in-frame deletion of 195 nucleotides into the 5' end of v-mht/mil, the results demonstrate that in the presence of an inactive v-myc oncogene, the 5'-deleted v-mht/mil oncogene fails to transform chicken embryo fibroblasts. Therefore, it is likely that avian primary fibroblasts lack a cellular component that serves as a critical substrate/target for v-mht/mil-induced cellular transformation.
 ...
PMID:Mutagenesis of the v-mht/mil oncogene in avian carcinoma virus MH2. 178 24

Tiazofurin and retinoic acid synergistically induced differentiation and inhibited colony formation in HL-60 human promyelocytic leukemia cells in cell culture. The synergism was the result of different mechanisms of action, since the effect of tiazofurin, unlike that of retinoic acid, was prevented by addition of guanosine. Since it has been shown that tiazofurin down-regulated the expression of c-Ki-ras oncogene, and retinoic acid that of the myc oncogene, the joint impact of these drugs is of clinical interest particularly in end-stage leukemia where the therapeutic usefulness of tiazofurin has recently been demonstrated.
 ...
PMID:Synergistic action of tiazofurin and retinoic acid on differentiation and colony formation of HL-60 leukemia cells. 196 20

The v-myc oncogenes of chicken retroviruses (including MC29) bear point mutations relative to chicken c-myc. These mutations result in several amino acid differences in the encoded proteins. We have used recombinant murine retroviruses containing various myc alleles to analyse the myelomonocytic transforming potential of the myc oncogene. The myc alleles used were MC29 v-myc, chicken c-myc, chimeric genes combining 5' sections of v- or c-myc with 3' sections of c- or v-myc, and mouse c-myc. The same retroviral vector (based on the genome of Moloney leukemia virus) was used for each allele and the genes were translated from genomic message. By infecting the primary mouse tissues, bone marrow, peritoneal-derived macrophages and mixed embryonic tissue with the recombinant viruses, variation was found in the transforming efficacy of these alleles: v-myc was most effective, followed by the two chimeric genes, whereas c-myc (chicken or mouse) was least effective in eliciting myelomonocytic transformation. Viral gag sequences were not necessary for this transformation. In each case, the transformed monocytes were growth factor-dependent and non-immortal. However, v-myc transformed monocytes (though not monocytes transformed by other myc alleles) were able to progress to an immortal, growth factor-independent phenotype. Our results indicate that v-myc is far more effective than c-myc in eliciting myelomonocytic transformation; that this is due to combinatorial effects of 5' and 3' mutations in the v-myc gene; and that secondary events in addition to these mutations are required for transformation of myelomonocytic cells to an immortal, tumorigenic phenotype.
 ...
PMID:Transformation of murine myelomonocytic cells by myc: point mutations in v-myc contribute synergistically to transforming potential. 264 46

Some of the current critical issues in the tiazofurin treatment of end-stage leukemia were presented and discussed. 1. Tiazofurin infusions (daily X 10 to 15) provided remissions in 50% of end-stage leukemic patients. The remissions, of 1 to 10 months' duration, varied from antileukemic effect or hematologic improvement to complete response and complete remission. The total survival of the responding patients was from about 1 to 15 months. 2. Our administration of tiazofurin in a 60-min infusion by pump decreased the incidence and severity of toxicity. 3. It was shown that tiazofurin dose does not need to be escalated at each relapse. Depending on the biochemical and hematological response in this novel protocol, 2,200 to 4,400 mg/m2 tiazofurin appeared to be sufficient to provide remissions. 4. A new role was identified for allopurinol, originally given to decrease uric acid in the plasma. Allopurinol markedly increased plasma hypoxanthine concentrations which competitively inhibited the activity of the salvage enzyme, guanine phosphoribosyltransferase, in the blast cells. Thus, the elevated hypoxanthine plasma levels inhibited guanine salvage. To maintain high hypoxanthine levels allopurinol (100 mg) was given every 4 to 6 hr. This provided combination chemotherapy with tiazofurin which inhibited IMP dehydrogenase activity and blocked the de novo biosynthesis of guanylates in the blast cells. 5. Preliminary evidence was obtained in the patients that tiazofurin induced differentiation of the bone marrow. Recent studies also showed that tiazofurin down-regulated the expression of the c-Ki-ras oncogene in K562 erythroleukemic cells. Therefore, tiazofurin treatment provides an impact by chemotherapy, induced differentiation, and, if applicable, through down-regulation of the ras oncogene. 6. Novel aspects of tiazofurin treatment include rational targeting and a continuously monitored trial by measurement of the activity of IMP dehydrogenase and of GTP and TAD concentrations in blast cells and of tiazofurin and hypoxanthine in plasma. 7. Since tiazofurin has not yet achieved lasting remissions in patients nor terminal differentiation of leukemic cells it probably will be advantageous to combine tiazofurin with other drugs to provide synergism. In preclinical tissue culture studies in HL-60 cells synergy was observed with retinoic acid. This may be of interest because retinoic acid also caused differentiation and down-regulation of the myc oncogene.
 ...
PMID:Critical issues in chemotherapy with tiazofurin. 269 55

Oncogenes have been intimately associated with the genesis of human neoplasms. A particularly useful system to study the mechanism of tumorigenesis is a small group of avian retroviruses that carry two oncogenes. These viruses causes acute leukemias and can transform hematopoietic cells in vitro. The mechanisms by which viral oncogenes affect the growth control and differentiation of their target cells is now understood in fair detail for two of these virus strains. In the avian erythroblastosis virus AEV, the v-erbB oncogene deregulates the growth control of erythroid precursors, while verbA blocks their terminal differentiation into erythrocytes. Based on the findings that v-erbB oncogene corresponds to a mutated growth factor receptor gene and that v-erbA corresponds to a mutated hormone receptor gene, models have been developed that explain the function of these two oncogenes on a molecular basis. The myelomonocytic leukemia virus MH2 acts by a completely different mechanism. In this case, the v-myc oncogene stimulates the proliferation of macrophage-like cells, while the v-mil gene stimulates them to produce their own growth factor, thus leading to autocrine growth. It will be interesting to determine whether the type of mechanisms of oncogene cooperativity elucidated for acute leukemia viruses are also operative during leukemogenesis in humans.
 ...
PMID:[Oncogenes and the origin of leukemia. Acute avian leukemia viruses]. 284 86

Infection of established (IL-3)-dependent hematopoietic cell lines with Abelson murine leukemia virus (A-MLV) abrogates their requirement for IL-3 and leads to non-autocrine growth factor-independent cells. We were interested to determine whether A-MLV can induce IL-3 independence also in non-established cells. To obtain long-term cultures of diploid myelocytes, splenic hematopoietic cells were first infected with MMCV, a murine retrovirus carrying the avian v-myc oncogene. These cultures were superinfected with A-MLV. In three independent experiments, the first growth factor-independent cells appeared between 18 and 43 days after superinfection with A-MLV and represented .02-1% of the population. Furthermore, the cultures that became growth factor-independent were monoclonal for integration of the v-abl gene. These results indicate that the acquisition of growth factor-independence after superinfection of v-myc-expressing cells with A-MLV is a rare event. The low frequency of growth factor-independent cells was not due to a low percentage of infected cells, since 15-25% of the cells were infected with A-MLV after 7 days. The first appearance of growth factor-independent cells coincided with crisis in the cultures, as indicated by a high incidence of cell death and a reduced overall growth rate of the cell populations. These growth factor-independent cells exhibited variable karyotypes, including many that were near-triploid to near-tetraploid. In summary, growth factor-independence induced by super-infection with A-MLV, like that induced by double-infection with v-myc- and v-H-ras-containing viruses, is associated with unstable karyotypes. The growth factor-independent cells show variable ploidy characteristic of cells which survived crisis.
 ...
PMID:The induction of growth factor-independence in murine myelocytes by oncogenes results in monoclonal cell lines and is correlated with cell crisis and karyotypic instability. 285 Nov 20

Lymphoid tumors induced by a recombinant murine retrovirus carrying the v-myc oncogene of avian MC29 virus were characterized. The Moloney murine leukemia virus myc oncogene (M-MuLV (myc], carried by an amphotropic MuLV helper, induced tumors in NIH Swiss and NFS/N mice after a relatively long latency (8 to 24 wk). Tumor masses appeared in the thymus, spleen, and lymph nodes. Flow cytometry of the tumor cells indicated that approximately 50% were positive for Thy 1.2. Most of these tumors also expressed one or more other cell surface markers of thymocytes and mature T cells (CD4, CD8). Southern blot hybridization revealed genomic rearrangements for the TCR beta genes. The TCR beta analysis suggested that the M-MuLV(myc)-induced Thy 1.2+ tumors were derived from somewhat less mature cells than tumors induced by M-MuLV, which is a classical non-acute retrovirus lacking an oncogene. The remainder of the M-MuLV(myc)-induced tumors were Thy 1.2-, but they were positive for Ly-5 (B220) and also for MAC-2. The Thy 1.2- tumors were characteristically located in the thymus. However, they were negative for TCR beta gene rearrangements. Some, but not all, of the Thy 1.2- tumors contained rearrangements for Ig genes. Additionally, they typically expressed mRNA specific for B but not for T cells. Thus, these thymic tumors had characteristics of the B cell lineage. Tumor transplantation experiments demonstrated that the Thy 1.2- tumor cells could reestablish in the thymus and spleen of irradiated hosts, and low level expression of the Thy 1 molecule was observed in the thymus but not the spleen on the first passage. After serial passage, one Thy 1- tumor altered its cell surface phenotype to Thy 1low B220-.
 ...
PMID:Characterization of lymphoid tumors induced by a recombinant murine retrovirus carrying the avian v-myc oncogene. Identification of novel (B-lymphoid) tumors in the thymus. 290 39

Injection of newborn mice with mixtures of wild-type moloney murine leukemia (Mo-MuLV) virus and other recombinant retroviruses harboring the myc oncogene alone or in combination with the H-ras oncogene resulted in a 100% incidence of lymphatic leukemias from which permanent cell lines could be established in vitro. These cells are immunoglobulin (Ig)-, Thy-1+BP- and CD8-CD4- indicating that they are early thymocytes. Such transformed pre-T lines lack retroviral myc and ras genes but occasionally possess proviral insertion near to their endogenous myc and pim genes. We show that both Ig heavy chain (Igh) and T cell receptor (TcR) genes are rearranged in most of these lines. In some cases, a primary recombination was followed by a secondary rearrangement at the same locus. We show that VT gamma genes can rearrange outside of their known cluster suggesting that TcR gamma diversification in such pre-T cells may be different to that in more mature T cells. Ig D-JH recombinations may precede TcR gene recombination in these early T cell lines, and some but not all express sterile Cmu transcripts. Some of these lines express surface heterodimers that appear composed of alpha and beta chains that can be immunoprecipitated with a monoclonal anti-T3 antibody but not with the anti-V beta 8 monoclonal antibody F23.1. This established pre-T cell line represents novel biological material for the dissection of T cell development and function analogous to A-MuLV transformed pre-B cells.
 ...
PMID:Rearrangement and expression of T cell receptor and immunoglobulin loci in immortalized CD4-CD8- T cell lines. 296 19


1 2 3 Next >>