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)

Patients with chronic lymphocytic leukemia (CLL) treated with adenovirus (Ad)-CD154 (CD40L) gene therapy experience reductions in leukemia cell counts and lymph node size associated with induction of the death receptor Fas (CD95). CD4 T cell lines can induce apoptosis of CD40-activated CLL cells via a CD95 ligand (CD95-L)-dependent mechanism. To examine whether CD95-L was sufficient to induce cytolysis of CD40-activated CLL cells, we used Chinese hamster ovary cells transfected with CD95-L as cytotoxic effector cells. CD40-activated CLL cells were initially resistant to CD95-mediated apoptosis despite high-level expression of CD95. However, after 72 h, CLL cells from seven of seven patients became increasingly sensitive to CD95-mediated apoptosis. This sensitivity correlated with a progressive decline in Flice-inhibitory protein (FLIP), which was induced within 24 h of CD40 ligation. Down-regulation of FLIP with an antisense oligonucleotide or a pharmacologic agent, however, was not sufficient to render CLL cells sensitive to CD95-mediated apoptosis in the 24-72 h after CD40 activation. Although the levels of pro-Caspase-8 appeared sufficient, inadequate levels of Fas-associated death domain protein (FADD) and DAP3 may preclude assembly of the death-inducing signaling complex. Seventy-two hours after CD40 ligation, sensitivity to CD95 and a progressive increase in FADD and DAP3 were associated with the acquired ability of FADD and FLIP to coimmunoprecipitate with the death-inducing signaling complex after CD95 ligation. Collectively, these studies reveal that CD40 ligation on CLL B cells induces a programmed series of events in which the cells initially are protected and then sensitized to CD95-mediated apoptosis through shifts in the balance of the anti- and proapoptotic proteins FLIP and FADD.
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PMID:Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. 1189 Dec 78

Depletion of T lymphocytes from allogeneic bone marrow transplants successfully prevents the development of graft-versus-host disease (GvHD) but is associated with impaired engraftment, immunosuppression, and abrogation of the graft-versus-leukemia effect. We therefore explored the possibility of selectively eliminating alloreactive T cells by CD95/CD95L-mediated activation-induced cell death (AICD) in a major histocompatibility complex allogeneic murine model system. Activation of resting or preactivated T lymphocytes from C3H/HeJ (H-2(k)) mice was induced with irradiated BALB/cJ (H-2(d)) mouse-derived stimulators. Substantial decrease (> or = 80%) of proliferative and lytic responses by activated alloreactive T cells was subsequently achieved by incubating the mixed lymphocyte culture with an agonistic monoclonal antibody to CD95, and residual T cells recovered did not elicit alloreactivity upon challenge to H-2(d). Depletion of alloreactive T lymphocytes by AICD was specific because reactivity to an I-A(d)-restricted ovalbumin (OVA) peptide by OVA-specific CD4(+) T cells mixed into the allogeneic T-cell pool and subjected to induction of AICD in the absence of OVA peptide could be preserved. Adoptive transfer of donor-derived allogeneic T lymphocytes, depleted from alloreactive T cells by AICD in vitro, in the parent (C3H/He) to F(1) (C3H/He x BALB/c) GvHD model prevented lethal GvHD. The results presented suggest that alloreactive T cells can effectively be depleted from allogeneic T cells by induction of AICD to prevent GvHD and might introduce a new strategy for the separation of GvH-reactive T cells and T cells mediating antiviral and possibly graft-versus-leukemia effects.
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PMID:Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death. 1192 98

B-lineage acute leukaemia cells are generally resistant to CD95-mediated apoptosis. In this report, the CD95-resistant B-leukaemia lines SEM, RS4;11, and REH were used to investigate the mechanisms of resistance to CD95-signalling. We found that interferon-gamma (IFN-gamma) treatment increased the presence of high molecular weight forms of CD95 in these cells as judged by Western analysis, and treatment of protein extracts with Peptide: N -glycosidase F indicated that the majority of high molecular weight forms were due to N-linked glycosylation. Treatment of whole cells with neuraminidase from Vibrio cholerae substantially reduced the relative molecular mass of CD95 observed after IFN-gamma treatment and partially sensitized the three leukaemia lines to CD95-mediated death. To further characterize the different steps of oligosaccharide processing that may regulate CD95 signalling, the leukaemic cells were treated with IFN-gamma and the glycosidase inhibitors castanospermine, 1-deoxymannojirimycin (DMM), and swainsonine. Treatment with DMM, a mannosidase inhibitor, efficiently reduced the appearance of high molecular weight forms of CD95 after IFN-gamma treatment, and sensitized SEM and REH cells to CD95-mediated death. However, the IFN-gamma-induced increases of CD95 on the cell surface were not altered by treatment with any of the glycosidase inhibitors, suggesting that the generation of complex oligosaccharide structures is not required for trafficking of CD95, but may instead be used as a mechanism of partially blocking CD95 signalling in these cells. In conclusion, IFN-gamma treatment of the B-lineage leukaemia lines provides a novel, inducible system for the further characterization of post-translational modifications involved in modulating sensitivity to CD95-signalling.
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PMID:Interferon-gamma increases the expression of glycosylated CD95 in B-leukemic cells: an inducible model to study the role of glycosylation in CD95-signalling and trafficking. 1209 25

Fas/CD95 is a type-I membrane glycoprotein, which inducesapoptotic cell death when ligated by its physiological ligand. We generated previously hyperproliferative sublines derived from the human T-cell leukemia Jurkat, Jurkat-ws and Jurkat-hp, which lost Fas/CD95 surface expression. We have now observed that the total amount of Fas protein is similar in the sublines and in the parental cells, indicating that in the sublines Fas remains in an intracellular compartment. We have found that the protein is directed toward lysosomes in the sublines, where it is degraded. This defect in the secretory pathway correlates with loss of polyunsaturated fatty acids from cellular lipids, and with the lack of expression of endophilin-I and CtBP/BARS, enzymes that regulate vesicle fission by catalyzing the acylation of arachidonate into lysophosphatidic acid. In addition, great multillamer bodies, which contained acid phosphatase activity, absent in the parental Jurkat cells, were observed by transmission electron microscopy in the sublines.
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PMID:Lack of Fas/CD95 surface expression in highly proliferative leukemic cell lines correlates with loss of CtBP/BARS and redirection of the protein toward giant lysosomal structures. 1213

Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.
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PMID:Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation. 1214 93

The factors determining the growth and survival of cells in B chronic lymphocytic leukemia (CLL) have remained poorly understood. We investigated the effects of optimal mitogen combinations (OMCs) on the expression of 26 surface membrane antigens among 33 CLL patients. The seven OMCs used were selected after pre-testing 14 combinations of (1) S. aureus Cowan I (SAC), (2) interleukin-2 (IL-2), (3) tumor necrosis factor alpha (TNF-alpha) and (4) 12-O-tetradecanoylphorbol 13-acetate (TPA; also known as phorbol 12-myristate 13-acetate or PMA). In flow cytometry we revealed that OMCs induced statistically highly significant upregulation of the expression of CD5, CD11c, CD19, CD22, CD23, CD25, CD38, CD40, CD45, CD45RO, CD95, CD126, CD130 and FMC7, and downregulation of CD20 and CD124 expression. Interestingly, the expression of CD27, CD45RA, CD79b, CD80, CD122 and that of the immunoglobulin gene superfamily members CD21, Ig-kappa, Ig-lambda, Ig-delta and Ig-micro were not significantly affected under similar conditions. The expression of several antigens was co-regulated, suggesting common regulatory pathways. These antigens include CD11c/CD5, CD11c/CD22, CD11c/CD126, CD11c/FMC7 as well as CD27/CD45, CD27/CD45RA and CD27/CD79b. Upregulation of surface antigen expression, induced by OMCs, should be applicable in antibody therapy in vitro and in vivo, and in negative stem cell selection for autotransplantation. Furthermore, the current strategy to enhance cell surface antigen expression may be a versatile tool to raise humoral and cell-mediated host defense against CLL cells. Upregulation of proteins mediating positive growth signals (eg CD25, CD40) and negative signals or apoptosis (eg CD95) may be used to sensitize cells to chemotherapy and programmed cell death.
Leukemia 2002 Sep
PMID:Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells. 1220 Jun 83

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Deltapsi(m)), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Deltapsi(m), and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.
Leukemia 2002 Sep
PMID:CD20-induced B cell death can bypass mitochondria and caspase activation. 1220 Jun 88

Advances in molecular biology and immunology have identified means to activate the immune response against leukemia-associated antigens. Recent studies indicate that the stealth-like phenotype of leukemia cells can be reversed through transfer of genes encoding recombinant membrane-stabilized proteins of the tumor necrosis factor (TNF) imily, such as the one encoding CD154, the ligand for CD40. A phase I clinical trial using autologous CD154-transduced leukemia cells as a cellular vaccine has provided encouraging results. Treatment not only appears capable of inducing a cellular anti-leukemia immunity, but also may have a direct effect on leukemia cells by inducing latent sensitivity to Fas (CD95)-dependent leukemia-cell apoptosis. Phase II studies currently are underway using multiple injections of autologous leukemia cells made to express recombinant CD154 via gene transfer. Conceivably, we may be entering an era of effective gene therapy for hematologic malignancies.
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PMID:Immune and cell therapy of hematologic malignancies. 1243 Aug 62

Although arsenic trioxide (As2O3) has been shown to be an effective anticancer agent for acute promyelocytic leukemia (APL), its mechanisms of action as well as its effect on other leukemias than APL remain unclear. We studied in vitro effects of As2O3 at low concentrations (1.0-2.0 microM) on two human leukemia/lymphoma cell lines, HL-60, an acute myeloid leukemia cell line, and RL, a B-cell lymphoma cell line. As2O3 inhibited proliferation of HL-60 cells and RL cells to the similar degree to the reported inhibition by an APL cell line, NB4. As2O3-treated cell lines exhibited typical morphologic changes of apoptosis such as nuclear condensation and apoptotic bodies, and a cell cycle arrest at the subG1 phase. As2O3-treated cell lines also showed upregulation of CD95/CD95L expression and activation of caspases 8 and 3. Treatment of these cells with anti-CD95 antibodies capable of blocking the CD95 signaling pathway ameliorated As2O3-induced apoptosis. These data suggest that As2O3 can inhibit growth of leukemia/lymphoma cells by inducing the cell cycle arrest and apoptosis that is partially mediated by the CD95/CD95L system.
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PMID:Arsenic trioxide induces apoptosis in leukemia/lymphoma cell lines via the CD95/CD95L system. 1268 47

A series of human acute lymphoblastic leukemia (ALL) cell lines, BALM-19, -20, -21, -22, -23 (BALM 19-23) and BALM-26 were established from a patient with B-cell characteristics of ALL L2 type. All cell lines were derived from bone marrow specimens, BALM 19-23 from a sample taken at diagnosisand BALM-26 from one at relapse. Like the original leukemia cells, the established lines present various B-cell characteristics, being positive for cell surface immunoglobulin (Ig) chains but also for nuclear terminal deoxynucleotidyl transferase; hence the cell lines should be assigned to B-cell category B-IV. As a unique feature, the cell lines expressed the CD33 myeloid antigen in addition to the common B-cell markers. Heterogeneous antigen expression among the different cell lines was found regarding CD35, CD39, CD45RA, CD78 and CD95. The malignant nature of the cell lines was documented by negativity for the Epstein-Barr virus and by the occurrence of clonal non-random structural chromosome abnormalities. The patient's serum showed hypercalcemia, prompting further investigation of the established cell lines which expressed parathyroid hormone related peptide (PTHrP) mRNA as examined by reverse transcriptase polymerase chain reaction. The established B-cell ALL sister cell lines, BALM 19-23 and BALM-26, could provide useful material for clarifying the pathogenesis of this type of B-cell malignancy. The scientific significance of this panel of cell lines lies in the availability of a series of clonally derived but phenotypically different sister cell lines established at different phases of the disease.
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PMID:Novel B-cell acute lymphoblastic leukemia sister cell lines BALM 19-23 and BALM-26 with interclonal proliferative and phenotypic heterogeneity from a patient with hypercalcemia. 1270 46


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