Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, a novel class of murine type C virus (MCF), some strains of which are highly oncogenic in the AKR acceleration test, has been isolated from premalignant and malignant thymuses of AKR mice. The biology of these viruses suggested that MCFs are the product of recombination between endogenous ecotropic and xenotropic viruses and, further, that the recombination has taken place within the envelope (env) gene which encodes the surface glycoprotein (gp70) of the virion. We have compared by tryptic peptide analysis, the gp70s of four MCF isolates with the gp70s of various possible parental viruses. In addition, we have compared the tryptic peptides of the gag gene products p30 and p15 from several of these viruses. The results allow the following conclusions: (i) the gp70s of the MCF viruses are not identical to one another and are different from the gp70s of the possible parental viruses tested; (ii) the MCF virus gp70s have tryptic peptides in common with xenotropic virus gp70s as well as with ecotropic virus gp70s; and (iii) the gap region protein, p30, of the MCFs tested is identical to p30 of AKR ecotropic virus (Akv-1 or Akv-2) and distinct from p30 of xenotropic viruses, suggesting that the 5' end of the recombinant viruses is of Akv origin. The findings are discussed with respect to the possible role a recombinant virus might play in leukemogenesis in AKR mice.
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PMID:Biochemical evidence that MCF murine leukemia viruses are envelope (env) gene recombinants. 20 Sep 28

As an approach to evaluating the contribution of classes of endogenous viral sequences to leukemogenesis, a genomic library was prepared from the highly tumorigenic AKR SL12.3 cell line and screened for env-containing proviruses. An extensive battery of virus-derived probes and specific oligonucleotide probes were used to segregate 83 positive clones into related groups. The nonecotropic endogenous retroviruses were identified as members of the polytropic, modified polytropic, or xenotropic groups. At least three unique xenotropic proviruses were detected that differed from the published xenotropic sequence within a variable region of the 5' portion of env. Changes among the xenotropic proviruses included relative insertions and/or deletions that maintain an open reading frame and hence the potential to encode viable envelope gene products. Several recombinant viruses were also detected. Recombination was not random and primarily involved the formation of mink cell focus-inducing class I retroviruses via recombination between polytropic elements and ecotropic virus. One other recombinant was detected which contained ecotropic virus sequences in the 5' region encoding p15 of an otherwise xenotropic provirus. An interesting observation was the finding that certain clones contained more than one provirus within the average 20-kb cloned insert. This would not be expected if integration were totally random. The de novo recombinant proviruses identified here provide a series of potential candidates to be evaluated for their contribution to the tumorigencity of the SL12.3 cell line.
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PMID:Characterization of endogenous and recombinant proviral elements of a highly tumorigenic AKR cell line. 187 Jan 92

An approach toward elucidation of the mechanisms of action of mammalian leukemia viruses has been made by the generation in tissue culture of recombinant viruses between a potent murine leukemia virus (MuLV), Rauscher-MuLV, and an endogenous xenotropic mouse type-C virus, BALB:virus-2, without known malignant potential. Using a double selection system devised to select against the temperature-sensitive (ts) lesion associated with a mutant of Rauscher-MuLV and the xenotropic host range of BALB:virus-2, recombinant viruses were obtained at frequencies ranging from 0.01 to 0.1%. Recombinant viruses were identified on the basis of the type specific antigenic determinants in the translational products of gag (p15, p12, p30, and p10 proteins), pol (reverse transcriptase), and env (gp70 glycoprotein) genes. By this approach, the partial genetic maps of a large number of recombinants were obtained. The fact that p10 of Rauscher-MuLV ts 25, the mutant utilized, was the only protein uniformly lacking in recombinant viruses, localized the lesion inhibiting gag precursor cleavage in this mutant at the carboxy terminus of its gag gene. The recombinant viruses demonstrated two host range phenotypes as defined by Fv-1 host cell restriction. In each case, NB-tropic recombinants possessed the p30 of BALB:virus-2 p30. Thus, it was possible to assign the site of Fv-1 action at, or closely linked, to the viral p30. The target within the viral genome of a second host restriction was also mapped. A serum factor, previously shown to specifically inactivate xenotropic virus infectivity, was demonstrated to exert its action on the viral env gene product. The system described here allows the generation of specific recombinant genotypes that should be useful in defining those regions of the viral genome involved in leukemogenesis.
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PMID:Viral genes involved in leukemogenesis. I. Generation of recombinants between oncogenic and nononcogenic mouse type-C viruses in tissue culture. 615 14

Recombinant viruses were generated in tissue culture between Rauscher murine leukemia virus (MuLV) temperature-sensitive (ts) mutants restricted at different steps in virus replication and a mouse endogenous xenotropic virus, BALB:virus-2. Mutants used included ts 28, a late mutant which releases noninfectious viruses at 39 degrees C, and ts 29, a double mutant with a ts lesion in its reverse transcriptase and a late block affecting virus budding. Immunological typing of the translational products of clonal recombinant viruses made it possible to establish their partial genetic maps and localize regions of the viral genome affected by different ts lesions. Recombinants involving Rauscher MuLV ts 28 invariably contained BALB-virus-2 p15, p12, and p30 proteins, localizing the late defect in replication by this mutant to the 5' moiety of the viral gag gene. All ts 29-derived recombinants contained the entire BALB:virus-2 gag and pol genes. Substitution of the pol gene is in agreement with the reported thermolability of Rauscher MuLV ts 29 reverse transcriptase (Tronick et al., J. Virol. 16:1476-1482, 1975). Substitution of the gag gene suggests that internal structural proteins are actively involved in the virus budding processing. Rauscher MuLV recombinants were used to establish the genetic map of the Rauscher MuLV genome by T1 oligonucleotide fingerprinting analysis. Detection of Rauscher MuLV T1 oligonucleotides in representative recombinant viruses, whose protein phenotypes were established by immunological techniques, permitted their assignment to specific regions of the viral genome. The genetic map of Rauscher MuLV generated in these studies should be useful for identifying and characterizing the viral gene(s) involved in leukemogenesis.
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PMID:Recombinants between temperature-sensitive mutants of rauscher murine leukemia virus and BALB:virus-2: genetic mapping of the Rauscher murine leukemia virus genome. 626 12

To identify the genetic events that may play an important role in leukemogenesis of childhood ALL, we report for the first time the allelotyping of childhood ALL. Twenty-four cases of childhood ALL were screened for loss of heterozygosity (LOH) using 101 highly polymorphic microsatellite markers, which are distributed among all autosomal chromosomes. For LOH analysis on both chromosomes 9 and 12, 54 childhood ALL samples were examined. The most frequent allelic loss was found on chromosomal arm 9p, where 20 of 50 (40%) informative samples showed LOH. Moreover, nearly 30% of samples that did not have either homozygous deletions or point mutations of the putative tumor suppressor genes CDKN2/INK4A/p16 and INK4B/p15 on chromosomal arm 9p had LOH at D9S171. Loss of chromosomal arm 12p was also frequent (26%). Mutational analysis suggested that the altered gene on 12p is not the cyclin-dependent kinase inhibitor p27/Kip1, which is also on 12p. Several other regions that had LOH included 1p, 4q, 5p, 6q, 7p, 8p, 9q, 10q, 13q, 17p, 17q, 18q, 19q, and 22q. Of 24 patients, 19 (79%) showed allelic loss on at least one chromosomal arm. Samples of two patients (8%) showed LOH on almost all chromosomes. Fractional allelic loss, calculated for each sample as the total number of chromosomal arms lost/total number of arms with information, showed a median value of 0.04 and a mean of 0.123 (range, 0 to 0.95). This fractional allelic loss is lower than those reported for many solid tumors. This analysis shows the extreme power of LOH analysis using microsatellite markers in childhood ALL.
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PMID:Allelotype analysis of childhood acute lymphoblastic leukemia. 758 4

The cytogenetic findings of therapy-related myeloid leukemia (t-ML) in three children are presented. These included one male patient with acute lymphoblastic leukemia (ALL) who underwent bone marrow transplantation and developed therapy-related myeloproliferative disease (t-MPD) in the female-donor hematopoietic cells 2.5 years after receiving radiation and epipodophyllotoxin therapy for ALL testicular relapse. Bone marrow leukemic cell karyotype revealed 46,XX,add (11)(p15) and a normal female karyotype in the peripheral blood lymphocytes. The other two children, one with ALL and one with ganglioneuroblastoma, developed fatal t-MPD and therapy-related acute myeloblastic leukemia (t-AML) preceded by myelodysplastic syndrome (t-MDS), respectively, 5 years after diagnosis, following administration of alkylating agents and irradiation. Monosomy 7 was present in both, and was combined with inv(3)(q21q26) in the second patient. Our review of the cytogenetic findings in 91 previously reported pediatric patients with t-ML suggested that the involvement of 11p15 and 3q21-->23, 3q24-q26 with or without a combination of translocation 11q23 and -7/7q-, respectively, are nonrandom aberrations of t-ML in children. Comparison of the chromosomal changes in t-ML between the pediatric and an adult series revealed some differences which may result from differences in treatment modalities and which, in addition, may indicate a possible role of genetic and/or age-dependent factors in the pathogenesis of therapy-related leukemogenesis in children.
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PMID:Involvement of 11p15 and 3q21q26 in therapy-related myeloid leukemia (t-ML) in children. Case reports and review of the literature. 803 58

p16 INK4A and/or p15 INK4B genes are frequently deleted in leukemias and other cancers. We have established a novel pre-B acute lymphoblastic leukemia (ALL) cell line (JKB2) with a chromosomal translocation between 9p2l and 14q32, on which p16INK4A/p15INK4B and heavy chain immunoglobulin (Ig) genes, respectively, are located. Homozygous deletions of P16INK4A/p15INK4B genes in JKB2 cells were confirmed by polymerase chain reaction, and their protein products were not detectable by Western blotting. Therefore JKB2 is the first example of an immunoglobulin heavy chain translocation associated with deletions of these genes. In JKB2 cells, cyclin-dependent kinase(CDK)4 and CDK6 formed complexes with cyclin D, due to the lack of p16, triggering phosphorylation of retinoblastoma protein (pRB) and continuous cell proliferation. Moreover, the growth of JKB2 cells was partially inhibited by TGF beta or IL-7, accompanied by decreased CDK4 and CDK6 expression, increased p2l and p27 expression, decreased p27 binding to CDK4/CDK6, and increased binding of p27 to CDK2. In addition, IL-7 both inhibited proliferation and induced differentiation of JKB2 cells. These studies suggest that a t(9;14)(p21;q32) chromosomal translocation can result in deletion of both p16 INK4A and p15 INK4B genes in pre-B ALL, and that the JKB2 cell line therefore provides a model for the study of leukemogenesis related to abnormalities in chromosome 9p2l. Moreover, they suggest that TGF-beta can, suppress JKB2 cell growth in a p15-independent mechanism.
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PMID:A novel pre-B acute lymphoblastic leukemia cell line with chromosomal translocation between p16(INK4A)/p15(INK4B) tumor suppressor and immunoglobulin heavy chain genes: TGFbeta/IL-7 inhibitory signaling mechanism. 884 92

The mechanism of leukemogenesis and persistent lymphocytosis (PL; benign expansion of B lymphocytes) in cattle infected with bovine leukemia virus (BLV; a retrovirus closely related to human T-cell leukemia virus type 1) is unknown; however, the immune system likely plays an important role in controlling the outcome of infection. In this study, we compared T-cell competence in serologically positive alymphocytotic (AL) animals with T-cell functions in animals with progressive stages of infection, PL and tumor bearing (TB). Dramatic differences were observed in lymphocyte proliferation to recombinant proteins encoded by BLV gag (p12, p15, and p24) and env (gp30, and gp51) genes in different disease stages. Lymphocytes from AL cattle recognized an average of three of five recombinant proteins per animal. Expansion of antigen pulsed lymphocytes in interleukin-2 increased protein recognition to almost five per animal. In contrast, lymphocytes from PL and TB animals failed to recognize any BLV recombinant proteins. Short-term T-cell cultures from the PL group expanded in interleukin-2, as well as the PL and TB cells cultured in indomethacin (3 to 6 microg/ml), increased the average of recognized proteins per animal to one. Cells proliferating to BLV antigens were CD4+ T lymphocytes, as shown by cell depletion studies. The positive effect of indomethacin suggests involvement of prostaglandin E2 as a negative regulatory factor in the later stages of disease. Thus, for the first time, advancing stages of BLV infection were correlated with decreased T-cell competence, providing deeper insight into pathogenesis of retroviral infections.
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PMID:Progression to persistent lymphocytosis and tumor development in bovine leukemia virus (BLV)-infected cattle correlates with impaired proliferation of CD4+ T cells in response to gag- and env-encoded BLV proteins. 889 78

Chromosome band 9p21-22 is one of the most common targets for deletions in cancer. The p16 tumor suppressor gene maps to this region and is inactivated in a wide variety of tumor cell lines and primary tumors. However, in some of the neoplasms with frequent 9p21 loss of heterozygosity (LOH), a structurally and functionally normal p16 is found suggesting that this gene might not be the primary or only target for inactivation. To define the smallest region of overlap of deletions at chromosome band 9p21-22 and to clarify the involvement of p16, p15 and the IFN cluster gene in lymphoblastic leukemias, we used a multiplex polymerase chain reaction to construct a detailed map of deletions at 9p21-22. We studied DNA from 30 lymphoblastic leukemia patients and nine cell lines using 10 genes/markers that map to this region, including four STS markers located between p16 and D9S171 (STS1, STS2) or between p16 and IFNalpha (STS3, STS4). We found that the size of the deletions in this region is variable and that the commonly deleted region spans at least 400 kb; it includes the p16 gene but excludes the IFN gene cluster and the p15 gene. The identification of this commonly deleted region enables a more focused search for other putative tumor suppressor gene at 9p21 which could be relevant to leukemogenesis.
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PMID:The commonly deleted region at 9p21-22 in lymphoblastic leukemias spans at least 400 kb and includes p16 but not p15 or the IFN gene cluster. 900 86

The inv(11)(p15q22) is a recurrent chromosomal abnormality associated with de novo and therapy-related myeloid malignancies. Here we report the molecular definition of this chromosomal aberration in four patients. Positional cloning showed the consistent rearrangement of the DDX10 gene on chromosome 11q22, which encodes a putative RNA helicase. The translocation targets the NUP98 gene on 11p15, a member of the FG peptide repeat nucleoporin family. In DDX10 and NUP98, the inv(11) breakpoints occurred within two introns of each gene and the two genes merged in-frame to produce the chimeric transcripts characteristic of this translocation. Although two reciprocal chimeric products, NUP98-DDX10 and DDX10-NUP98, were predicted, only NUP98-DDX10 appears to be implicated in tumorigenesis. DDX10 is predicted to be involved in ribosome assembly. NUP98 has been identified as a nuclear pore complex protein and a target of chromosomal translocation in acute myeloid leukemia through the t(7;11)(p15;p15) translocation. The predicted NUP98-DDX10 fusion protein may promote leukemogenesis through aberrant nucleoplasmic transport of mRNA or alterations in ribosome assembly.
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PMID:The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. 916 30


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