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)

Human T-cell leukemia virus type I causes adult T-cell leukemia and tropical spastic paraparesis, and its regulator protein Tax has been implicated in the pathogenic activity of human T-cell leukemia virus type I. Tax activates transcription of viral and cellular genes through specific enhancers: the 21-bp enhancer of human T-cell leukemia virus type I, the nuclear factor kappa B (NF-kappa B)-binding site of the interleukin 2 receptor alpha gene, and the serum-responsive element of c-fos. Tax binds to enhancer-binding proteins including cAMP-responsive element-binding protein, cAMP-responsive element modulator, transcription factor NF-kappa B p50 and p67SRF, and associates with each enhancer DNA indirectly. In addition to this mechanism, we report here that Tax binds to inhibitory factor kappa B gamma (I-kappa B) gamma, which forms a complex with NF-kappa B protein heterodimer p50-p65 or homodimer p50-p50 and retains them in the cytoplasm. Tax binding to I-kappa B gamma induces nuclear translocation of NF-kappa B p65. In association with this nuclear translocation of p65, transcription directed by the kappa B enhancer is strongly activated. Tax binds to the ankyrin motifs of I-kappa B gamma, suggesting its possible interaction with many other proteins carrying ankyrin motifs contributing to various regulatory processes. This is a different mechanism of transcriptional activation by the oncoprotein Tax and seems to be independent from the trans-activation through indirect binding to enhancer DNAs.
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PMID:Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor kappa B and induces nuclear translocation of transcription factor NF-kappa B proteins for transcriptional activation. 817 Sep 51

T cell growth factor receptor, interleukin-2 receptor alpha chain (IL-2R alpha) is constitutively expressed on human T-cell leukemia virus type-1 (HTLV-1) infected T cells. We have established L cell lines which express both IL-2R alpha and the Rex protein of HTLV-1. We found that IL-1R alpha mRNA is stabilized in a cell line, Ltk/1-2a, which expresses a high amount of the Rex protein. In the presence of lower amounts of Rex, stabilization of the mRNA was not observed. These results may well explain the mechanism by which most of the lymphocytes infected with HTLV-1 escape from malignant transformation.
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PMID:Stabilization of interleukin-2 receptor alpha chain mRNA by HTLV-1 Rex in mouse L cells: lower amounts of Rex do not stabilize the mRNA. 829 27

Single-chain immunotoxins anti-Tac(Fv)-PE40 and anti-Tac(Fv)-PE40KDEL, composed of variable domains of the anti-Tac monoclonal antibody and truncated forms of Pseudomonas exotoxin, have shown potent cytotoxic activity against malignant peripheral blood mononuclear cells (PBMCs) from adult T-cell leukemia (ATL) patients originating from the Caribbean. However, several clinically important issues have not previously been addressed. These include the potential of soluble interleukin 2 receptor in ATL patients to block immunotoxin effectiveness, the relative sensitivity of malignant lymph node cells (LNCs) versus PBMCs, the effect of an immunotoxin with a prolonged half-life, and finally whether ATL cells from patients in Japan have toxin sensitivity equal to those of the Caribbean patients. To resolve these questions, we studied 32 malignant PBMC and LNC samples from 30 ATL patients from Japan. PBMCs from 27 of 27 patients were very sensitive with 50% inhibition of protein synthesis achieved with 0.02-0.85 ng/ml (0.3-13 pM) of anti-Tac(Fv)-PE40KDEL or anti-Tac(Fv)-PE40. LNCs had sensitivity very similar to that of PBMCs in the five patients tested. The fully recombinant immunotoxin, anti-Tac(Fab)-PE40, which has 8-10 times the t1/2 alpha and beta compared to the Fv-immunotoxins, was also very cytotoxic toward cells from 27 of 27 patients tested with 50% inhibition of protein synthesis of 0.08-25 ng/ml. It was found that purified soluble interleukin 2 receptor added to the cytotoxicity assay decreased the cytotoxic activity of anti-Tac(Fv)-PE40KDEL or anti-Tac(Fab)-PE40, but that 1 x 10(4) units/ml or less had minimal competitive effects. It was found that ATL patients who have responded even incompletely to conventional chemotherapy have soluble interleukin 2 receptor levels lower than this at posttreatment. We conclude that recombinant immunotoxins containing anti-Tac(Fv) are effective against Japanese ATL PBMCs or LNCs and might be most effective if used in vivo after conventional chemotherapy. If it is found in humans that the effectiveness of single-chain recombinant toxins is limited by short half-life, anti-Tac(Fab)-PE40 should be considered as an alternative agent.
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PMID:Cytotoxicity of recombinant Fab and Fv immunotoxins on adult T-cell leukemia lymph node and blood cells in the presence of soluble interleukin-2 receptor. 831 62

The relationship between interleukin-1 (IL-1) and interleukin-2 (IL-2) production and immunophenotype marker profiles was studied in a panel of 29 leukaemia and human T cell lymphotropic virus-1 (HTLV-1)-transformed T cell lines. Culture supernatants from six of the 29 T cell lines tested increased IL-2 production by the MOLT-16 cell line in a manner similar to that of rIL-1 alpha or rIL-1 beta. The enhancing activity in the cell culture supernatants was inhibited by antibody against IL-1 alpha. Anti-IL-1 beta antibody had no inhibitory effect. All the cell lines producing IL-1 alpha had characteristics of activated mature T cells. They were terminal deoxyribonucleotidyl transferase (TdT)-, CD4+, CD8-, HLA-DR+ and all were strongly positive for IL-2R alpha (Tac antigen) expression. However, none of the IL-1 alpha producing cell lines secreted detectable IL-2. A significant quantity of IL-2 was found, after stimulation with phytohaemagglutinin, in supernatants from nine of the 29 cell lines tested. The majority of IL-2 producing cell lines originated from less mature, non-activated T cells, as they were characterized by the expression of TdT, lack of HLA-DR antigens and > 50% had no detectable IL-2R alpha. The results thus show that separate, phenotypically different leukaemia and HTLV-1-transformed T cell clones produce IL-1 alpha and IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production of interleukin-1 alpha and interleukin-2 by separate, phenotypically different leukaemia and human T cell lymphotropic virus-1-transformed T cell clones. 831 80

Rabbits can be infected with human retroviruses such as human T-cell leukemia virus-1 (HTLV-1) and human immunodeficiency virus (HIV), and provide useful animal models to study retroviral diseases such as adult T-cell leukemia and HIV. Previously we have succeeded in generating monoclonal antibodies (mAbs) against rabbit CD4, CD5 and CD11a antigens. To make this animal species more amenable to cellular and molecular studies, we have attempted to extend the panel of mAbs against rabbit CD antigens. Here we report on the generation of three neutralizing mAbs against interleukin-2 receptor alpha chain (IL-2R alpha) (CD25), Kei-alpha 1 (IgG2b), Kei-alpha 2 (IgG2a) and Kei-alpha 3 (IgG1). They specifically recognize the rabbit Mr 55,000 IL-2 binding protein, IL-2R alpha, and completely inhibit both high- and low-affinity IL-2 binding to F648b cells that express IL-2R alpha as well as IL-2R beta. The use of mAb Kei-alpha 1 confirmed that the rabbit IL-2R alpha is not only a low-affinity IL-2R on its own but also an essential component of high-affinity IL-2R as found in other animal species, and that rabbit activated T cells including HTLV-1-transformed cell lines express high levels of the IL-2R alpha. Together with mAbs against various rabbit CD antigens that we reported previously, these neutralizing mAbs to IL-2R alpha will be valuable for studies of human retrovirus infections, such as those induced by HTLV-1 or HIV, in rabbits.
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PMID:Generation of monoclonal antibodies to the rabbit interleukin-2 receptor alpha chain (CD25) and its distribution in HTLV-1-transformed rabbit T cells. 837 Jun 51

To ascertain whether the tumor cells can regulate the host immune systems through the production of the cytokines or their receptors, we examined the expressions of tumor necrosis factor alpha (TNF alpha), tumor necrosis factor beta (TNF beta), interleukin 2 (IL-2) and interleukin 2 receptor alpha chain (IL-2R alpha) on the human cancer cell lines by Northern blot analysis. We used K562 (leukemia cell line), MCF-7 (breast cancer cell line), LS180, HT29 (colon cancer cell lines), SH101 (gastric cancer cell line) and PH101 (pancreas cancer cell line). Expressions of TNF alpha, TNF beta and IL-2 mRNA were not detected in any of the tumor cell lines. However, 1.4 and 3.5 kilobases of the IL-2R alpha mRNA were expressed in the PH101 cells, but not in the other five cell lines. Furthermore, IL-2R alpha was detected on the cell surface of the PH101 cells by the flow-cytometric analysis with an anti-IL-2R alpha monoclonal antibody. Interestingly, the soluble IL-2R alpha (sIL-2R alpha) was found in the conditioned media obtained from the PH101 cell culture with a sandwich enzyme immunoassay. Moreover, the sIL-2R alpha secreted from the PH101 cells blocked the IL-2 dependent lymphocyte proliferation. These results indicate that the expression of IL-2R alpha on PH101 might suppress the IL-2 induced lymphocyte proliferation.
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PMID:The expression and biological activity of IL-2 receptor on a human pancreas cancer cell line. 850 43

Malignant cells of hematopoietic origin often express a variety of different growth factor receptors and antigens on their surface, at levels much higher than normal cells. These malignant cells can be selectively targeted with Pseudomonas exotoxin (PE) derivatives directed by interleukins 2, 4 and 6, and by Fv fragments of monoclonal antibodies to interleukin 2 receptor (IL2R) subunits, CD22 and other antigens present on these cells. Anti-Tac(Fv)-PE38, a single-chain recombinant immunotoxin which targets cells bearing the IL2Ra, is furthest along in preclinical development and is being prepared for clinical testing in patients with IL2Ra-positive leukemia, lymphoma and Hodgkin's disease.
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PMID:Targeting Pseudomonas exotoxin to hematologic malignancies. 856 7

The interleukin-2 receptor alpha chain (IL-2R alpha) is a T-cell growth factor receptor and is known to be induced in helper T cells by infection with human T-cell leukaemia virus type-1 (HTLV-1). The Rex protein of HTLV-1 has been shown to stabilize IL-2R alpha mRNA. Although the 3' untranslated region of many RNA has been regarded as a key element for stabilization, we found that the first 300 bases of the IL-2R alpha protein coding sequence were necessary for stabilization of the mRNA. As the first 201 bases were not sufficient for this effect, we conclude that the bases at position 201-300 downstream of the AUG start are important for stabilization.
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PMID:The 5' coding sequence of IL-2 receptor alpha chain mRNA mediates mRNA stabilization by HTLV-1 Rex. 856 20

Human T-cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T-cell leukemia and lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. We examined whether HTLV could productively infect human hematopoietic progenitor cells. CD34+ cells were enriched from human fetal liver cells and cocultivated with cell lines transformed with HTLV-1 and -2. HTLV-1 infection was established in between 10 and >95% of the enriched CD34+ cell population, as demonstrated by quantitative PCR analysis. HTLV-1 p19 Gag expression was also detected in infected hematopoietic progenitor cells. HTLV-1-infected hematopoietic progenitor cells were cultured in semisolid medium permissive for the development of erythbroid (BFU-E), myeloid (CFU-GM), and primitive progenitor (CFU-GEMM, HPP-CFC, or CFU-A) colonies. HTLV-1 sequences were detected in colonies of all hematopoietic lineages; furthermore, the ratio of HTLV genomes to the number of human cells in each infected colony was 1:1, consistent with each colony arising from a single infected hematopoietic progenitor cell. Severe combined immunodeficient mice engrafted with human fetal thymus and liver tissues (SCID-hu) develop a conjoint organ which supports human thymocyte differentiation and maturation. Inoculation of SCID-hu mice with HTLV-1-infected T cells or enriched populations of CD34+ cells established viral infection of thymocytes 4 to 6 weeks postreconstitution. Thymocytes from two mice with the greatest HTLV-1 proviral burdens showed increased expression of the CD25 marker and the interleukin 2 receptor alpha chain and perturbation of CD4+ and CD8+ thymocyte subset distribution profiles. Hematopoietic progenitor cells and thymuses may be targets for HTLV infection in humans, and these events may play a role in the pathogenesis associated with infection.
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PMID:Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo. 864 41

DNA motifs that encode for specific transcriptional regulatory sequences (TRS) when engineered adjacent to the structural protein coding domain of a suicide enzyme can provide cell-lineage specific protein expression. The disparate up-regulation of several genes in adult T-cell leukemia (ATL) versus HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), seropositive carriers (SPC) and uninfected normals may reflect events at the molecular level related to leukemogenesis or to processes maintaining the heme-oncologic phenotype. Further, the genetic transduction of cytokine and receptor genes uniquely associated with ATL may provide targets for the development of leukemia-specific gene therapies aimed at exploiting differences in the production of certain growth factors and growth factor receptors. Comparisons of the transcriptional and translational levels of interleukin-2 receptor alpha chain (IL-2R alpha), transforming growth factor-beta 1 (TGF-beta 1) and intracellular adhesion molecule-1 (ICAM-1) in ATL, HAM/TSP, and SPC and in several control populations revealed selectively up-regulated expression in ATL. We evaluated the feasibility of using lymphoid-specific TRS to activate herpes simplex virus thymidine kinase (HSVtk) to achieve selective cytotoxicity in leukemias expressing terminal deoxynucleotidyl transferase (TdT). Selective and efficient leukemic cell killing was produced and suggests that similar chimeric gene constructs containing TRS elements for IL-2R alpha, TGF-beta 1, or ICAM-1 may prove useful in designing gene therapies to treat ATL.
Leukemia 1997 Apr
PMID:Pleiotropic expression of heterologous cytokine/receptor genes in HTLV-1 associated diseases: candidate TRS for chimeric gene therapy. 920 5


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