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)

Moloney murine leukemia virus (Mo-MuLV) genomic mRNA codes for two gag precursors by alternative initiations of translation. An AUG codon governs the synthesis of the retroviral capsid proteins precursor, whereas a CUG codon directs the synthesis of a glycosylated cell surface antigen, the gross cell surface antigen. Control of the relative synthesis of the two precursors is crucial for MuLV infectivity and pathology. Furthermore, the MuLV mRNA leader sequence is very long and should inhibit translation according to the classical scanning model. This suggests a different translation initiation mechanism allowing gag efficient expression. We demonstrate, by using bicistronic vectors expressed in COS-7 cells, that the Mo-MuLV mRNA leader drives translation initiation by internal ribosome entry. We have localized the internal ribosome entry site (IRES) between the two initiation codons. This 126 nucleotide long IRES implies an oligopyrimidine tract located 45 nucleotides upstream of AUG codon. UV cross-linking and affinity chromatography experiments show that the PTB/p57 splicing factor specifically interacts with this oligopyrimidine tract. The MuLV IRES controls alternative translation initiation by activating the capsid protein precursor expression. This gag translational enhancer could exist in other retroviruses.
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PMID:Alternative translation initiation of the Moloney murine leukemia virus mRNA controlled by internal ribosome entry involving the p57/PTB splicing factor. 765 11

C57BL/6 mice can generate a type-specific and class IH-2Kb-restricted CTL response against histocompatible AKR/Gross murine leukemia virus (MuLV) cell surface antigen positive (GCSA+) tumor cells. These anti-AKR/Gross MuLV CTL are also known to lyse SC.Kb/623 target cells expressing the molecular MuLV clone AKR623 (derived from the endogenous ecotropic MuLV provirus emv-11). To help identify AKR623 viral epitopes recognized by these CTL, four chimeric proviruses were constructed from two parental plasmids, pAKR623 and pAK7. It has been shown that SC.Kb/7 fibroblast targets expressing the emv-14-derived molecular clone AK7 are only poorly lysed by anti-AKR/Gross MuLV CTL. Data from experiments employing SC.Kb cells infected with the chimeras as targets against anti-AKR/Gross MuLV CTL supported the location of a previously identified immunodominant epitope located within the viral p15E transmembrane envelope protein, peptide TM134-141 (KSP-WFTTL). Furthermore, the use of Kb-motif-defined AKR623 encoded peptides together with data obtained using the chimeric viruses allowed the identification of three additional anti-AKR/Gross MuLV CTL epitopes. Peptides representing these epitopes, MA125-132 (RSALY-PAL), RT142-149 (SHRWYTVL), and RT456-463 (RMTHYQAM), are characterized herein with respect to their ability to confer lysis upon EMV- target cells and to stimulate tumor primed splenocytes in vitro. The identification and characterization of these additional epitopes allow for a better understanding of both the CTL response against GCSA+ tumor cells and the dysfunctional CTL response against EMV-14 and AK7.
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PMID:Major and minor Kb-restricted epitopes encoded by the endogenous ecotropic murine leukemia virus AKR623 that are recognized by anti-AKR/Gross MuLV CTL. 784 10

Donor marrow transplantation can cure chronic myelogenous leukemia (CML). Unfortunately, the procedure is associated with severe complications and is limited to the minority of potential recipients with suitably matched donors. Autologous marrow transplantation using negative selection approaches such as incubation with gamma interferon (IFN-gamma) can produce cytogenetic and clinical remissions, but they are often associated with recurrent evidence of leukemia. A primitive progenitor population can be separated from normal human marrow on the basis of morphologic characteristics and cell surface antigen expression. Cell populations with similar morphologic and phenotypic characteristics obtained by positive selection from the marrow of patients with CML appear to be benign. Benign primitive and committed progenitors selected in this fashion can be expanded ex vivo when cultured in a "Transwell" system which physically separates hematopoietic cells from stromal feeder layers. Positive selection and ex vivo cultivation of benign progenitors from CML marrow may provide a source of hematopoietic stem cells suitable for autologous marrow transplantation. Autologous natural killer (NK) cells obtained from the peripheral blood of patients with CML are of benign origin and have antileukemia activity. Interleukin 2 (IL-2) activated autologous NK cells may be used in post-transplant cellular therapy to prevent recurrence of CML.
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PMID:Chronic myelogenous leukemia: in search of the benign hematopoietic stem cell. 790 18

This review summarizes the changes in cell surface antigen expression during proliferation and differentiation of human erythroid progenitors. The content is based on our experimental data obtained from complement-mediated cytotoxicity assays against hematopoietic progenitors and a combined technique of sequential micromanipulations of paired daughter cells derived from erythroid burst-forming units (BFU-E) and immunostaining with a panel of monoclonal antibodies, as well as from current information. BFU-E has CD34, CD41a (platelet glycoprotein[GP]IIb/IIIa) and CD41b(GPIIb) antigens. Paired daughter cells derived from BFU-E have CD41a, CD41b, CD71 (transferrin receptor) and HLA-DR antigens, but not CD34 or CD33 antigen. The CD36 antigen (thrombospondin receptor or GPIV) is first expressed on the cells after 5 days of culture, in agreement with the report that the anti-CD36 positive fraction contained a greater part of the erythroid colony-forming units (CFU-E). The blood group A antigen is first expressed on cells from aggregates derived from BFU-E after 5 days of culture. Glycophorin A is expressed on cell surface after 7 days of culture when proerythroblasts first appear. Hemoglobin alpha is expressed after 8 days of culture and coincides with the first appearance of basophilic erythroblasts. This review provides useful information on the identification of leukemic cells from poorly differentiated acute leukemias such as early erythroblastic leukemia and acute megakaryoblastic leukemia, and is useful in the understanding of the commitment and differentiation of erythroid and megakaryocytic progenitors in normal hematopoiesis.
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PMID:Cell surface antigen expression in human erythroid progenitors: erythroid and megakaryocytic markers. 806 85

CD30 is a member of the tumor necrosis factor receptor superfamily. CD30 was originally described as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells. In this study, recombinant human CD30 ligand was expressed on the surface of CV-1/EBNA cells and tested for biologic activities on a variety of different CD30+ human lymphoma cell lines. CD30 ligand enhanced Ig secretion of Epstein-Barr virus (EBV)-immortalized, CD30+ lymphoblastoid B-cell lines, but not Burkitt lymphoma lines. Recombinant CD30 ligand enhanced proliferation of "T-cell-like" Hodgkin's disease-derived cell lines and an adult T-cell leukemia cell line, but not "B-cell-like" Hodgkin's disease-derived cell lines, CD30+, EBV-immortalized lymphoblastoid B-cell lines, or CD30+ and EBV+ tumor B-cell non-Hodgkin's lymphoma cell lines. In addition, CD30 ligand mediated reduction of proliferation and viability, by induction of cytolytic cell death, of CD30+, large-cell anaplastic lymphoma cell lines. Two new antibodies, M44 and M67, against the CD30 antigen demonstrated similar biologic activities to the CD30 ligand. Taken together, these data demonstrate pleiotropic biologic activities of the CD30 ligand on different CD30+ lymphoma cell lines and indicate that the CD30-CD30 ligand interaction might have a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.
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PMID:Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines. 816 76

We developed an IgG1 mouse monoclonal antibody (ONS-M21) directed against a cell surface antigen of medulloblastomas and gliomas in immunisation of mice with the ONS-76 medulloblastoma cell line. The antibody specifically reacted with medulloblastomas, supratentorial primitive neuroectodermal tumours (SPNETs) and gliomas, but not with other neuroectodermally derived tumours (neuroblastoma and melanoma) or with other kinds of tumours (meningioma, neurinoma, leukaemia, and small cell lung cancer). No reactivity was identified with normal body tissues, including peripheral blood cells. Characterisation of the ONS-M21 antigen showed that it was a trypsin-sensitive glycoprotein with a molecular weight of 80 kDa on SDS-PAGE. The pattern of reactivity and the biochemical properties of this antigen were different from those of other markers of medulloblastoma. These results indicate that ONS-M21 detects a new tumour-associated cell surface antigen specifically expressed by medulloblastomas, SPNETs, and gliomas. This is the first report that medulloblastomas may share common cell surface antigens with gliomas, although most studies have concluded that medulloblastoma has a predominantly neuronal phenotype. The lack of reactivity with normal tissue implies that ONS-M21 has potential applications as both a diagnostic tool and a therapeutic agent.
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PMID:Characterisation of a new mouse monoclonal antibody (ONS-M21) reactive with both medulloblastomas and gliomas. 821 97

The authors report two patients with large granular lymphocyte (LGL) expansion associated with rheumatoid arthritis corresponding to pseudo Felty's syndrome. These cells have natural killer and T cell surface antigen markers. LGL are a heterogeneous population and expansion of these cells is responsible for leukemia, which is generally a monoclonal proliferation. It has been suggested that Epstein-Barr virus (EBV) is a putative agent in this leukemia. No EBV DNA was found with a polymerase chain reaction analysis in the lymphocyte DNA of our two patients. Some cases of pseudo Felty's syndrome have exhibited a monoclonal pattern on Southern blot analysis of the T cell receptor. On the contrary, our two cases showed a polyclonal pattern with TCR beta chain Southern blot analysis. This fact, associated with the mild course seen in both over more than twenty years, suggest that pseudo Felty's syndrome is a disease with a good prognosis.
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PMID:Pseudo Felty's syndrome. A polyclonal disease with a favorable prognosis. Report of two cases with Southern blot analysis of TCR. 829 49

Prolymphocytic leukemia (PLL) is closely related to chronic lymphocytic leukemia (CLL), but present with distinctive clinical/laboratory features and associated with much worse prognosis. In this study, we generated three new IgG1-kappa monoclonal antibodies (MoAbs), termed SN8, SN8a and SN8b, by use of an unconventional approach, ie, by using an isolated B PLL antigen preparation to immunize mice. These MoAbs, particularly SN8, showed a highly selective reactivity to B PLL and B non-Hodgkin's lymphoma (NHL) among various human leukemia-lymphoma specimens tested; eg, SN8 was capable of effectively distinguishing B PLL from B CLL as well as from hairy cell leukemia (HCL) cell specimens. The cell surface antigen defined by the three MoAbs was determined to be a covalently linked heterodimeric glycoprotein complex (gp49/40) consisting of a 49,000 dalton (alpha-chain) and a 40,000-dalton component (beta-chain). Epitope comparison showed that the epitope defined by SN8 (SN8 epitope) is in close proximity to SN8a epitope but in a distant position from SN8b epitope. Western blot analysis showed that both SN8 and SN8a epitopes are on the beta-chain, but SN8b epitope was not detected on either the alpha- or the beta-chain of the reduced antigen in the same analysis. Binding of either SN8 or SN8b to the cell surface gp49/40 did not cause significant downregulation of the antigen expression whereas binding of SN8a to the antigen caused small (approximately 20%) decrease in the antigen expression. Among the various normal peripheral blood cells, only a subpopulation (6.0% to 24.2% among different specimens derived from different donors) of B cells reacted with the SN8 series MoAbs; these MoAbs showed no significant reactivity against T cells, granulocytes, monocytes, erythrocytes, and platelets. Minimal or no significant reactivity (0 to 2.6% among different specimens) was detected against normal bone marrow cells. Ricin A-chain conjugates of the three MoAbs are all strongly effective for specific killing of SN8 antigen-expressing leukemia cells in the absence of any potentiators; furthermore, the addition of 10 mmol/L NH4Cl, a potentiator, enhanced strongly the cytotoxic activities of the SN8, SN8a, and SN8b conjugates. Thus, each of the three MoAbs was effectively internalized after binding to the cell surface antigen.
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PMID:Three new monoclonal antibodies that define a unique antigen associated with prolymphocytic leukemia/non-Hodgkin's lymphoma and are effectively internalized after binding to the cell surface antigen. 841 5

Regulation of complement (C') dependent lysis of cells is attributed to certain membrane proteins. One of these is decay-accelerating factor (DAF), CD55, a 70kD glycosylated protein which functions to protect host cells from damage by autologous C'. We hypothesized that blockade of DAF function by a monoclonal antibody (mAb) could augment C'-dependent lysis mediated by another mAb to a cell surface antigen expressed on leukaemia cells. Thus, we tested the effects of the anti-DAF mAb 1C6 on the ability of both rabbit and human C' to lyse human leukaemia cells through activation by complement-fixing murine mAb. DAF antigen was highly expressed on most leukaemia cell lines and primary acute leukaemia blast cells tested. Murine mAb to CD15 (PM-81) and to gp 120 (AML-1-99), both IgM, also bound to the majority of myeloid and lymphoid leukaemia cells. Using human serum as a source of C', the addition of mAb 1C6 reduced by an additional 85-94% the numbers of clonogenic HL-60 (myeloid leukaemia) cells lysed by mAb PM-81 alone. Similarly, the addition of mAb 1C6 reduced by an additional 87% the numbers of HL-60 colonies eliminated by mAb AML-1-99 alone. Similar results were observed in an experimental purging model using the myeloid leukaemia cell lines HL-60, U937 or NB4 cells as targets. These results show that mAb 1C6 can effectively block the actions of DAF. In the presence of mAb 1C6, the cytotoxic activity mediated by human C' was similar to that of rabbit C'. These results show that increased tumour cell killing can be achieved through DAF blockade. This finding has relevance to clinical trials using C'-fixing mAb for purging bone marrow of occult tumour cells prior to autologous transplantation.
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PMID:Homologous restriction of complement-mediated cell lysis can be markedly enhanced by blocking decay-accelerating factor. 854 61

The gene transfer efficiency of human hematopoietic stem cells is still inadequate for efficient gene therapy of most disorders. To overcome this problem, a selectable retroviral vector system for gene therapy has been developed for gene therapy of Gaucher disease. We constructed a bicistronic retroviral vector containing the human glucocerebrosidase (GC) cDNA and the human small cell surface antigen CD24 (243 bp). Expression of both cDNAs was controlled by the long terminal repeat enhancer/promoter of the Molony murine leukemia virus. The CD24 selectable marker was placed downstream of the GC cDNA and its translation was enhanced by inclusion of the long 5' untranslated region of encephalomyocarditis virus internal ribosomal entry site. Virus-producing GP+envAM12 cells were created by multiple supernatant transductions to create vector producer cells. The vector LGEC has a high titer and can drive expression of GC and the cell surface antigen CD24 simultaneously in transduced NIH 3T3 cells and Gaucher skin fibroblasts. These transduced cells have been successfully separated from untransduced cells by fluorescence-activated cell sorting, based on cell surface expression of CD24. Transduced and sorted NIH 3T3 cells showed higher GC enzyme activity than the unsorted population, demonstrating coordinated expression of both genes. Fibroblasts from Gaucher patients were transduced and sorted for CD24 expression, and GC enzyme activity was measured. The transduced sorted Gaucher fibroblasts had a marked increase in enzyme activity (149%) compared with virgin Gaucher fibroblasts (17% of normal GC enzyme activity). Efficient transduction of CD34+ hematopoietic progenitors (20-40%) was accomplished and fluorescence-activated cell sorted CD24(+)-expressing progenitors generated colonies, all of which (100%) were vector positive. The sorted, CD24-expressing progenitors generated erythroid burst-forming units, colony-forming units (CFU)-granulocyte, CFU-macrophage, CFU-granulocyte/macrophage, and CFU-mix hematopoietic colonies, demonstrating their ability to differentiate into these myeloid lineages in vitro. The transduced, sorted progenitors raised the GC enzyme levels in their progeny cells manyfold compared with untransduced CD34+ progenitors. Collectively, this demonstrates the development of high titer, selectable bicistronic vectors that allow isolation of transduced hematopoietic progenitors and cells that have been metabolically corrected.
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PMID:Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, with bicistronic vectors. 861 47


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