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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal BALB/c mice were inoculated (ip) with a recombinant Moloney murine leukemia virus-TB. Majority of the inoculated mice developed lymphoma within 5-7 months post infection. The cells from splenic lymphomas were cultured and 3 continuous cell lines (GP1, GP2 and GP3) developed. GP1 was single cell cloned and characterized. Based on Thy 1.2 (98.4%) phenotypic marker, the cell line was categorized as T cell line. The percent positivity for different cell surface markers on analysis with FACS was 98.4, 4.8, 5.5, 2.2, 1.8, 1.2 and 9.5 for Thy 1.2, mu, L3T4, Lyt2, Ia, IL2R and PNA receptor, respectively. A total of 16.5% GP1 cells was also positive for Moloney murine leukemia virus envelope protein (gp 70). Incomplete retrovirus like particles were demonstrated in the cytoplasm of GP1 cells by electron microscopy. The cell line on inoculation(ip) in neonatal BALB/c mice produced lymphomic lesions in almost all the vital organs of the mice.
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PMID:Characterization of a continuous lymphocyte cell line derived from BALB/c mice inoculated with a recombinant Moloney murine leukemia virus-TB. 145 11

An autocrine mechanism of proliferation may play a significant role in the leukemogenesis of adult T-cell leukemia, a mature T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-I). To further delineate the role of HTLV-I and the interleukin 2 (IL2) system in the transformation process, human primary lymphocytes were infected by cocultivation with lethally X-irradiated MT2 cells in the presence or absence of human rIL2; the polymerase chain amplification reaction was used to examine quantitatively the expression of HTLV-I, IL2, and IL2R alpha mRNAs during early and late proliferation phases that displayed polyclonal (days 7 to 49) and oligoclonal (days 100 to 150) proviral integration, respectively. IL2 mRNA and IL2 activity were transiently expressed during the polyclonal phase but were undetectable at later time points. IL2R alpha mRNA expression remained at a constitutively high level throughout the examined time course. Viral transcripts were detectable at each time point. Expression of the tax-rex mRNA was inversely related to IL2 mRNA levels; it was low early in the polyclonal phase but increased 30-fold with the development of oligoclonality. In addition, paraformaldehyde-fixed HTLV-I-producing cells activated peripheral blood lymphocytes. These data suggest that HTLV-I activates human T lymphocytes. However, IL2 expression is transient, indicating a limited involvement of an IL2 autocrine growth loop in the transformation process. Lastly, another viral determinant, in addition to the trans activator tax, may be important in HTLV-I-induced T-cell proliferation.
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PMID:Temporal regulation of viral and cellular gene expression during human T-lymphotropic virus type I-mediated lymphocyte immortalization. 207 56

The Tax protein of human T-cell leukemia virus is a potent transcriptional activator of viral and cellular genes, including the genes for interleukin 2 and interleukin 2 receptor alpha chain (IL2R alpha). The NF-kappa B protein has been implicated in Tax-mediated activation of IL2R alpha gene expression. We show that activation of NF-kappa B by Tax is an indirect process that requires prior activation of a preexistent factor that is present in lymphoid cells. Deletion mutagenesis revealed that the carboxyl-terminal acidic region of Tax is required for activation of IL2R alpha-directed gene expression but dispensable for activation of the long terminal repeat (LTR). Our findings suggest that activation of viral and cellular gene expression by Tax is achieved through a cascade of events that involves multiple protein-protein associations and that the specificity of these associations is conferred through different domains of the Tax protein.
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PMID:Activation of NF-kappa B by the HTLV-I trans-activator protein Tax requires an additional factor present in lymphoid cells. 248 94

The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/J mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis.
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PMID:Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice. 304 1

The tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the transforming properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. To address the early consequences of HTLV-1 tax function, we have constructed fusion proteins containing tax sequence either aminoterminal (taxER) or carboxy-terminal (ERtax) of the hormone binding domain of the human estrogen receptor (ER). Addition of estrogen or the antagonist hydroxytamoxifen to Jurkat T-cells expressing these constructs led to the trans-activation or responsive promoters and upregulation of cell surface markers CD28, CD69 and CD5 but not CD25 (IL2R-alpha subunit) or B7 (ligand for CD28). Additional stimulation of the T-cell receptor CD3 complex, led to the upregulation of CD25. B7 was upregulated by concomittent activation of ERtax and CD3 or CD28 pathways. These events were in part reversible upon withdrawal of hormone and inactivation of ERtax. Severe inhibition of proliferation, and apoptosis was observed with cells which had been subjected to short term (3 days) activation of the tax fusion proteins and the CD3 complex. Induction of ERtax activity for longer than 3 days promoted cell death independently of CD3 stimulation. Co-stimulation through the CD28 cell surface molecule did not suppress induction of apoptosis.
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PMID:Immediate effects of reversible HTLV-1 tax function: T-cell activation and apoptosis. 783 27

Interleukin 2 (IL2) receptors (IL2R's) are found on malignant cells in many human leukemias and lymphomas and are expressed by activated T cells in many autoimmune disorders. Anti-Tac(Fv), a single-chain protein composed of the variable heavy and light domains of the anti-IL2R monoclonal antibody anti-Tac, can be genetically fused to derivatives of Pseudomonas exotoxin (PE) or diphtheria toxin (DT) to form potent immunotoxins. We have shown that anti-Tac(Fv) binds to low affinity IL2R's on fresh chronic lymphocytic leukemia (CLL) and adult T-cell leukemia (ATL) cells and can target either toxin to kill those cells. Anti-Tac(Fv)-PE40, containing the truncated form of PE without its binding domain, was cytotoxic to malignant cells from 8 of 8 ATL patients tested, with IC50's ranging from 0.11 to 5.5 ng/ml. Anti-Tac(Fv)-PE40KDEL, a derivative of anti-Tac(Fv)-PE40 which contains the KDEL carboxyl terminus, was more cytotoxic toward cells from all ATL patients and also killed CLL cells from 8 of 16 patients. DT388-anti-Tac(Fv), containing amino acids 1-388 of DT fused to the amino terminus of anti-Tac(Fv), was less cytotoxic than anti-Tac(Fv)-PE40 on ATL cells from 4 of 5 patients, but was cytotoxic toward CLL cells from 12 of 16 patients. DT388-IL2, where IL2 is substituted for anti-Tac(Fv), is similar to DAB389IL2, an IL2-toxin currently in clinical trials. DT388-IL2 and DAB389IL2 differ by only a few amino acids and have equal cytotoxic activity. DT388-IL2 was cytotoxic toward ATL cells from all patients tested, but usually required much higher concentrations than anti-Tac(Fv)-PE40 and was poorly active against CLL cells. Thus, recombinant toxins containing anti-Tac(Fv) are cytotoxic toward freshly isolated CLL and ATL cells and will be studied further as potential therapy for IL2R-related disorders.
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PMID:Recombinant single-chain immunotoxins against T and B cell leukemias. 802 11

We have investigated the characteristics of IL2R alpha gene induction in untransformed murine T cells. Induction of IL2R alpha mRNA by TCR/CD3 ligands in a murine T cell clone and in short-term splenic T cell cultures was inhibited by protein synthesis inhibitors and by CsA. This result was contrary to previous observations in JURKAT T leukemia cells and human peripheral blood T cells, suggesting a difference in the mechanisms of IL2R alpha gene induction in these different cell types. The CsA sensitivity of IL2R alpha mRNA induction represented a direct effect on the TCR/CD3 response, and was not due to CsA-sensitive release of the lymphokines IL2 or tumour necrosis factor alpha (TNF alpha) and consequent lymphokine-mediated induction of IL2R alpha mRNA. The NF-kappa B site of the IL2R alpha promoter was essential for gene induction through the TCR/CD3 complex, and the induction of reporter plasmids containing multimers of this site was significantly inhibited by CsA. Northern blotting analysis indicated that while the p65 subunit of NF-kappa B was constitutively expressed and not appreciably induced upon T cell activation, mRNA for the p105 precursor of p50 NF-kappa B was induced in response to TCR/CD3 stimulation and this induction was sensitive to CsA. Electrophoretic mobility shift assays and antiserum against the p50 subunit of NF-kappa B indicated that p50 was a component of the inducible nuclear complex that bound to the IL2R alpha kappa B site. Appearance of the kB-binding proteins was insensitive to CsA at early times after activation (approximately 15 min), but was partially sensitive to CsA at later times. Based on these results, we propose that the NF-kappa B site of the IL2R alpha promoter mediates at least part of the CsA sensitivity of IL2R alpha gene induction in untransformed T cells, possibly because de novo synthesis of p105 NF-kappa B is required for sustained IL2R alpha expression.
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PMID:Cyclosporin A sensitivity of the NF-kappa B site of the IL2R alpha promoter in untransformed murine T cells. 802 23

The human T-cell leukemia virus type I (HTLV-I) and HTLV-II Tax proteins are potent transactivators of viral and cellular gene expression. Using deletion mutants, the downstream parathyroid hormone-related protein (PTHrP) promoter is shown to be responsive to both HTLV-I and HTLV-II Tax as well as the AP1/c-jun proto-oncogene. Transactivation of PTHrP by Tax was seen in T cells but not in B-cell lines or fibroblasts. A carboxy terminal Tax deletion mutant was deficient in transactivation of both the PTHrP and IL2R alpha promoters but not the HTLV-I long terminal repeat (LTR). Exogenous provision of NFkB rescued IL2R alpha expression but not the PTHrP promoter. Thus, HTLV-I Tax, HTLV-II Tax, and c-jun transactivate PTHrP and may contribute to the pathogenesis of hypercalcemia in adult T-cell leukemia.
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PMID:Cell-type-specific transactivation of the parathyroid hormone-related protein gene promoter by the human T-cell leukemia virus type I (HTLV-I) tax and HTLV-II tax proteins. 842 83

Two novel cell lines (JURL-MK1 and JURL-MK2) have been established from the peripheral blood of a patient in the blastic phase of chronic myelogenous leukemia. The cells grow in a single cell suspension with doubling times of 48 h (JURL-MK1) and 72 h (JURL-MK2). Cytogenetic analysis has shown that JURL-MK1 is hypodiploid whereas JURL-MK2 is near triploid and that both cell lines retain t(9;22). Moreover, JURL-MK1 and JURL-MK2 have a bcr/abl-fused gene with the same junction found in the patient's fresh cells, and both cell lines express the b3/a2 type of hybrid bcr/abl mRNA. The morphology and immunophenotype of these cell lines are reminiscent of megakaryoblasts. In both lines, a limited but consistent percentage of cells expresses gpIIbIIIa (CD41a), gpIIIa (CD61) and CD36, with no expression of gplb (CD42b), glycophorin A, hemoglobin and CD34. Both cell lines are clearly positive for CD33, CD43, CD45RO and CD63, while CD13, CD44, CD54, CD30 and CD40 are specific features of JURL-MK2. Among cytokine receptors, CD117/SCF-R is strongly displayed by a large fraction of JURL-MK1 cells but is hardly detectable on about 20% JURL-MK2 cells. Both cell lines are clearly positive for CD25/IL2R alpha, while a marked expression of CD116/GM-CSF-R and CDw123/IL3R alpha is restricted to JURL-MK2. Induction of cell differentiation in vitro has demonstrated that TPA is able to modulate the JURL-MK1 phenotype, causing an increased expression of platelet-associated antigens. The JURL-MK2 phenotype is easily modulated by both TPA and DMSO, which cause an increased expression of CD41a and CD117 accompanied by a decreased expression of CD30. Proliferation studies demonstrated that JURL-MK1 cell growth is enhanced by stem cell factor, while JURL-MK2 proliferation is unaffected by this cytokine. JURL-MK1 and JURL-MK2 are two novel cell lines with divergent biological features, representing a 'two-sided' model for investigating new aspects of megakaryocytopoiesis.
Leukemia 1997 Sep
PMID:JURL-MK1 (c-kit(high)/CD30-/CD40-) and JURL-MK2 (c-kit(low)/CD30+/CD40+) cell lines: 'two-sided' model for investigating leukemic megakaryocytopoiesis. 930 12

The alpha chain of the interleukin 2 receptor (IL2R alpha; Tac) was targeted in clinical trials with adult T cell leukemia using murine anti-Tac antibody. Of 19 patients, a single individual achieved a durable complete remission. The mechanism of this action by murine anti-Tac has not been defined. We examined the hypothesis that the maintenance of the long-term response after treatment might be related to induction of a network of anti-idiotypic antibodies, as proposed in other tumor settings. In contrast to anti-Tac non-responders, the patient was found to have produced a human anti-mouse antibody (HAMA) response, and specifically an anti-idiotypic (Ab2) response, that was readily detectable by standard assays 4 years after treatment. Using phage display antibody libraries, this response was shown to be monoclonal, consisting of a single IgG1,kappa antibody of moderate affinity. No evidence was found for anti-anti-idiotypic (Ab3) antibodies with reactivity for sTac, which might alternatively have maintained an autogenic human anti-Tac antibody response. An area of limited homology was noted between the Ab2 antibody and the IL2R in the domain of IL2 binding, but no binding of Ab2 to IL2 could be shown that might have reduced endogenous ligand (IL2) concentrations. Similarly, no anti-anti-idiotypic (T3) T cell response was detected. Thus, we are unable to confirm features of idiotypy that could suggest a role in maintaining an anti-tumor response by anti-Tac antibody therapy.
Leukemia 1998 Jun
PMID:Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody. 963 30


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