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)

The ability of acute myeloid leukaemia (AML) cells to acquire dendritic cell (DC)-like characteristics in vitro with a rapid culture method based either on the phorbol ester PMA or calcium ionophores has been studied in comparison to conventional AML-DC cultures with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), SCF, FLT3-L and IL-4. In all AML patients, antigen-presenting cells (APC) could be generated from leukaemic cells in 2 days by incubation with PMA or calcium ionophore (A23187 or ionomycin) in the presence as well as in the absence of IL-4. In 30 out of 36 patients APC could be generated after 2 weeks of culture in cytokine-enriched medium. AML-APC cultured with PMA or calcium ionophores immunophenotypically and functionally were at a more mature stage than those cultured in cytokine-enriched medium. The most mature APC were generated by calcium ionophore A23187 plus IL-4, as evidenced by the higher expression of CD40, CD80, CD86 and HLA-DR. Autologous T cell mediated cytotoxicity towards AML blast cells in vitro was observed in 2 cases tested. The persistence of cytogenetic abnormalities confirmed the leukaemic origin of the AML-APC. The generation of AML-APC was possible from freshly isolated as well as cryopreserved material. Our data show that generation of sufficient AML-APC by A23187 plus IL-4 is feasible, for vaccination purposes, in approximately 70% of AML specimens, offering a time-saving and cost-effective approach in preparing anti-leukaemia vaccines.
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PMID:Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia. 1253 36

Murine AIDS (MAIDS) develops in susceptible mouse strains after infection with the LP-BM5 murine leukemia virus (MuLV) complex that contains a mixture of defective (BM5def) and replication-competent viruses. While the BM5def virus is the causative agent in MAIDS, the replication-competent viruses in LP-BM5, including ecotropic MuLV (BM5eco), are required for BM5def propagation and thus function as helper viruses. We describe quantitative real-time RT-PCR assays for RNA encoded by the BM5def and BM5eco components of LP-BM5. The assays were used to standardize better the input doses of LP-BM5 viruses across viral preparations and to quantify BM5def and BM5eco gag RNA levels in spleen and blood cells from MAIDS-susceptible and -insusceptible infected mice. Spleens of MAIDS-susceptible infected mice harbored approximately similar levels of BM5def gag RNA as infected spleens of mice that are insusceptible to MAIDS due to lack of CD40. In contrast, the same infected spleens of CD40-deficient mice contained substantially higher (up to 10-fold) levels of BM5eco gag RNA compared with susceptible controls. Similar to that seen in spleen, infected blood of CD40-deficient mice contained similar levels of BM5def gag as susceptible strains, but increased levels (up to threefold) of BM5eco gag RNA. The assays described below can be used to characterize better the contributions of different functional viral components of the LP-BM5 mixture to the development of MAIDS.
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PMID:Quantitative analysis of LP-BM5 murine leukemia retrovirus RNA using real-time RT-PCR. 1256 53

We have utilized a free-solution isoelectric focusing technique (FS-IEF) to obtain chaperone-rich cell lysate (CRCL) fractions from clarified tumor homogenates and have previously reported on their vaccinating potential. To better understand the underlying mechanisms as well as to improve on the immunizing efficacy of tumor-derived chaperone complexes, in the present study we examined the effects of CRCL-loaded dendritic cells (DCs) against 12B1, an aggressive bcr-abl+ murine leukemia tumor. We found that DCs incubated with 12B1-derived CRCL had higher expression of CD40 and major histocompatibility complex class II (MHC-II) on their cell surface, produced more interleukin-12 (IL-12), and had superior immunostimulatory capacity in a mixed leukocyte reaction (MLR) when compared with DCs exposed to unfractionated tumor lysate or purified heat-shock protein 70 (HSP70). Vaccination of mice with 12B1 CRCL-pulsed DCs significantly prolonged their survival, with more than 80% of mice rejecting their tumors following a lethal challenge with live 12B1 compared with those immunized with tumor lysate or HSP70-loaded DCs. The protective immunity generated was tumor specific, long lasting, and both CD4+ and CD8+ T-cell dependent. Moreover, immunization with CRCL-loaded DCs resulted in a 75% cure rate in mice with pre-existing 12B1 tumors. Our findings indicate that CRCL has prominent adjuvant effects and is a very effective source of tumor antigen for pulsing DCs. FS-IEF-derived CRCL-pulsed DCs are a promising anticancer vaccine that warrants clinical research and development.
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PMID:Tumor-derived, chaperone-rich cell lysate activates dendritic cells and elicits potent antitumor immunity. 1257 9

Recently, leukaemia-associated antigens (LAA) recognized by T lymphocytes, such as Wilm's tumour-1 (WT-1) or pathogenesis-related protein-1 (PR-1), have been identified. For immunotherapies that employ antigen peptides, either alone or pulsed on dendritic cells (DC), the expression of human leucocyte antigen (HLA) molecules on the targeted leukaemic blasts (LB) is crucial. The co-stimulatory molecules CD80 and CD86 give the secondary signal to T lymphocytes that is necessary for the lysis of leukaemia cells, and CD40 enhances the efficacy of antigen presentation. Here, the expression of HLA-ABC, HLA-A2, HLA-DR, CD40, CD80 and CD86 was flow cytometrically examined in blood samples from 24 healthy volunteers (HV), 24 patients with newly diagnosed acute myeloid leukaemia (AML) and five patients with relapsed AML. The expression of HLA-ABC, CD40, CD80 and CD86 was significantly reduced on LB in comparison with monocytes of HV. HLA-A2 and HLA-DR expression was similar on LB and on monocytes of HV. In AML patients, the expression of HLA and CD86 molecules was significantly higher on LB than on CD33/CD34-negative monocytes. CD40 and CD80 molecules were deficient on AML blasts. The preservation of HLA molecules and CD86 on LB of the majority of AML patients at the time of diagnosis and even at relapse of the disease are prerequisites for LAA-targeted immunotherapies in these patients.
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PMID:Expression of human leucocyte antigens and co-stimulatory molecules on blasts of patients with acute myeloid leukaemia. 1264 70

The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.
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PMID:MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. 1268 28

CD40 ligand (CD40L) is a good candidate molecule for the immunotherapy of B cell malignancies including B-chronic lymphocytic leukemia (B-CLL), because it may increase the capacity of the malignant cells to present tumor antigens. However, efforts to manipulate expression of the human CD40L (hCD40L) molecule have foundered on problems associated with lack of consistent gene transfer into the malignant target cells. We now describe a new, highly reproducible method for inducing hCD40L surface expression on malignant B cells, which is dependent on intercellular transfer of the hCD40L protein from donor gene-modified fibroblasts to patient tumor cells. Ten B-CLL samples were cocultured with MRC-5 fibroblasts (a human embryonic lung cell line) previously transduced with an adenoviral vector encoding the hCD40L gene. The malignant cells expressed high levels of surface hCD40L, B7-1, B7-2, and ICAM-1 after coculture. Upregulation of B7-1 and B7-2 was cycloheximide inhibitable and was a consequence of CD40 activation. However, inhibition of protein synthesis had no effect on the ability of B-CLL cells to acquire surface expression of hCD40L. hCD40L surface expression required cell-to-cell contact, but was independent of CD40 engagement. hCD40L transfer was not mediated by membrane fusion. The transferred hCD40L was functionally intact and B-CLL cells expressing this molecule induced increased interferon-gamma production from autologous peripheral blood T lymphocytes. This approach does not use any direct gene transfer to primary leukemia cells and can readily be scaled up for production of clinical B-CLL vaccines.
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PMID:Bystander transfer of functional human CD40 ligand from gene-modified fibroblasts to B-chronic lymphocytic leukemia cells. 1271 65

We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) gene therapy with transgene-expressing myeloid progenitor cells (32DTNF-alpha) is effective in inhibiting the progression of leukemia with a lethal dose of murine 32Dp210 myeloid leukemia cells. Because TNF-alpha has been shown to induce the activation and maturation of dendritic cells (DCs), we investigated the effect of TNF-alpha secreted by transduced cells (32DTNF-alpha cells) on the activation of DCs and their role in the production of antileukemic cytotoxic T lymphocytes (CTLs). We demonstrate that administration of 32DTNF-alpha cells to the mice enhances the allo-stimulatory capacity of the splenic (CD11c+) and bone marrow-derived DCs in both mixed leukocyte response and CTL development. The enhanced allo-stimulatory capacity of splenic DCs from mice injected with 32DTNF-alpha cells correlated with increase in the cell-surface expression of the costimulatory molecules CD40, CD80, CD86, and major histocompatibility complex (MHC) class II molecules (I-Ak), and production of interleukin-12 (IL-12). Furthermore, administration of 32DTNF-alpha cells during immunization with irradiated 32Dp210 leukemia cells augmented the capacity of splenic DCs to stimulate antileukemic CTL response in spleen cells. Collectively, these data suggest that in vivo production of TNF-alpha by transduced cells enhances the phenotypic and functional activation of DCs, resulting in induction of a stronger antileukemic cytotoxic T-cell immune response.
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PMID:In vitro analysis of the antileukemic effect of tumor necrosis factor-alpha gene therapy with myeloid progenitor cells: the role of dendritic cells. 1282 12

Acute myeloid leukemia (AML) is a clonal disease of hematopoiesis with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Immunotherapy with dendritic cells (DCs) eliciting specific T cell responses to leukemia-associated antigens (LAAs) might be a therapeutic option. DCs must express HLA class I/II molecules and the costimulatory molecules CD40, CD80 and CD86 to effectively activate T cells for the subsequent lysis of leukemic blasts. The expression of these antigens on DCs generated from 15 AML patients (AML-DCs) and on DCs generated from 15 healthy volunteers (HV-DCs) was analyzed by FACS. All DCs displayed the typical morphology and tested negative for B, T and NK cell markers. The sustained mRNA expression of LAAs such as PRAME, RHAMM or WT-1 proved that the AML-DCs originated from AML blasts. Compared with AML blasts, the expression of CD40, CD80, CD86 and HLA-DR was upregulated during DC culture to a median of 80-98% on AML-DCs. HLA-ABC was preserved on AML-DCs (median 95%). Expression of CD40, CD80 and CD83 remained lower on AML-DCs than on HV-DCs. AML-DCs express at least one LAA and strongly express HLA and costimulatory molecules, the prerequisites for eliciting T cell responses. AML-DCs may play a role in vaccine-based immunotherapies for AML patients.
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PMID:Reconstitution of CD40 and CD80 in dendritic cells generated from blasts of patients with acute myeloid leukemia. 1286 19

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.
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PMID:Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL. 1290 78

Relapse of pediatric acute lymphoblastic leukemia (ALL) remains a significant clinical problem. The graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation indicates that immune mechanisms may play a role in the control of ALL blasts. In this study, we analyzed primary diagnostic and relapsed pre-B ALL samples for the surface expression of several molecules implicated in immune responses and for the induction of allogeneic T cell responses. There were no significant differences in the expression of CD11a, CD40, CD80 and CD86 or MHC classes I and II molecules between the diagnostic and relapsed samples. We found no significant differences in the overall ability of diagnostic and relapsed pre-B ALL samples to induce T cell proliferation and cytokine production. However, in the case of T cell responses induced by diagnostic ALL samples, there was excellent correlation between proliferation and production of all cytokines analyzed. In the case of relapsed samples, the only correlation obtained was with IL-5. This observation indicates that the nature of the immune response generated by relapsed ALL cells in an allogeneic setting differs from that obtained with diagnostic samples, suggests a biasing towards a Th2 response may contribute to the evasion of effective immune responses by relapsed ALL.
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PMID:Altered patterns of T cell cytokine production induced by relapsed pre-B ALL cells. 1292 52


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