Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The severe combined immunodeficient (SCID) mouse model is an important tool with which to study new strategies for treating hematologic neoplasia. For these experiments, a large number of human cell lines growing in SCID mice are a prerequisite. We describe a new Epstein-Barr virus (EBV)-positive B cell line, designated BEVA, with a complex karyotype including translocations t(14:18)(q32;q21) and t(4;11) (q21;q23) that meets this need. As demonstrated by Southern blot analysis, BCL2 at 18q21, but not MLL/ALL1 at 11q23, was involved in these translocations. BEVA cells coexpressed lymphoid (IgG-kappa, CD19, CD20, CD21, and CD24) and myeloid (CD11b, CD15, and CDw65) markers. Interestingly, the cell line was established from the bone marrow culture of a patient with acute myeloid leukemia (AML). Examination of bone marrow biopsy specimens suggested the presence of non-Hodgkin's lymphoma (NHL) in this patient in addition to AML. In vitro and in vivo growth characteristics of the BEVA cell line were compared with the previously described EBV-positive B cell line DoHH2, also carrying a translocation t(14;18)(q32;q21). These DoHH2 cells additionally expressed CD10, whereas, in contrast to BEVA cells, only a small population of DoHH2 cells showed expression of CD44. Both cell lines showed similar growth characteristics in vitro, but reacted differently to cytokines, including interleukin (IL)-4, IL-6, IL-7, and alpha-interferon (IFN). Upon inoculation in SCID mice, marked differences were observed in the dissemination patterns of the BEVA or DoHH2 cells. Although both cell lines circulated in the blood and were predominantly found in murine bone marrow and lymphoid tissues, DoHH2 cells infiltrated the murine spleens, whereas BEVA cells could only rarely be detected in these tissues. In contrast to DoHH2 cells, BEVA cells gave rise to tumor masses in liver, kidney, and para-aortal or mesenteric lymph nodes. The relationship between these in vitro differences and the observed differences in dissemination of both cell lines is discussed.
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PMID:Characterization of a novel malignant B cell line with t(14;18) and t(4;11) established from a patient with acute monoblastic leukemia. 929 3

Leukemic growth is determined by the balance of cell proliferation, differentiation and cell death. In vitro, the blasts of acute myelogenous leukemia (AML) proliferate under the influence of certain positive and negative regulators (cytokines). We conducted this study to determine whether cytokines could induce markers of cell death (FAS/Apo-1/CD95), of cell activation (HLA-DR) and cell adhesion (ICAM-1, CD54) in AML cell lines and primary AML samples. As inducers, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were chosen. At baseline, CD95 and CD54 were weakly and HLA-DR was strongly expressed. CD95 was induced by TNF in 6/12 myeloid leukemia cell lines, and by IFN in 9/12 cell lines. Taken together, CD95 was upregulated by at least one cytokine in 11/12 cell lines. HLA-DR was inducible in 10/12 cell lines, with IFN being more potent than TNF. CD54 showed the strongest induction: TNF resulted in a more than 20-fold induction in positive cell lines, and IFN resulted in a more than 20-fold induction. In primary AML samples, CD95 was induced in 14/14 samples examined, with TNF being more potent than IFN. HLA-DR expression was increased by IFN in 12/15 samples and by TNF in 11/13 samples. The inducibility of HLA-DR by IFN was inversely correlated with baseline expression. As in the cell lines, CD54 was induced in most cases of AML. In addition to the induction of surface markers by cytokines, the culture of leukemia cells with fetal calf serum increased the expression of these markers, especially CD95 and CD54. Our results demonstrate that CD95 is not downregulated when TNF binds to its receptors, but is induced in cell lines and patient samples. Despite the induction of expression of CD95 (all cases of AML and most cell lines), 7/8 myelogenous leukemia lines and 6/7 patient samples remained resistant to CD95 triggering by antibody or by CD95 ligand, which suggests a lesion in normal cell signaling. As a positive control, a T-cell line (Jurkat) with 60% to > 90% apoptotic cells after a 22 h incubation was used. The number of CD95-binding sites was not correlated with the induction of apoptosis. The resistance of most cases of AML to CD95 triggering despite inducible expression may also be related to leukemia-specific antagonists of CD95 signal transduction, and requires further investigation. Altogether, our results indicate that surface markers related to apoptosis, activation and adhesion can be induced on AML blasts, and could be relevant to treatment strategies that exploit ligand binding to these surface epitopes.
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PMID:Induction of death (CD95/FAS), activation and adhesion (CD54) molecules on blast cells of acute myelogenous leukemias by TNF-alpha and IFN-gamma. 938 99

Interferon consensus sequence binding protein (ICSBP) was first identified as a transcription factor of the interferon (IFN) regulatory factor family (IRF) which regulates expression of IFN-dependent genes by binding to DNA at specific sites, IFN-stimulated responsive elements. Analysis of ICSBP-deficient mice showed hematologic alterations similar to chronic myelogenous leukemia (CML) in humans and suggested a novel role for ICSBP in regulating proliferation and differentiation of hematopoietic progenitor cells. Here we show that ICSBP-mRNA expression is impaired in human myeloid leukemias: 27 of 34 CML patients (79%) and 21 of 32 patients with acute myeloid leukemia (AML) (66%) showed very low or absent transcript numbers of ICSBP. In contrast, only 2 of 33 normal volunteers (6%) showed low transcription of ICSBP (P < . 0001 both for CML and AML values). The lack of expression was not associated with lack of lymphatic cells, which normally have been shown to express ICSBP at the highest level. More detailed analysis showed an absence of ICSBP-mRNA also in sorted B cells derived from CML patients. To analyze whether ICSBP may be induced in leukemic cells, ex vivo experiments using a known inducer of ICSBP, IFN-gamma, were performed. Ex vivo treatment of primary CML cells using IFN-gamma resulted in induction of ICSBP transcripts. Furthermore, samples of CML patients during IFN-alpha treatment were analyzed. In 11 of 12 CML patients ICSBP-mRNA was inducible upon in vivo treatment with IFN-alpha, but decreased with progression of CML. Stable transfection of K-562 cell line with ICSBP led to no difference in bcr-abl expression in vitro, although two patients showed an inverse correlation between bcr-abl and ICSBP in vivo. These data suggest that lack of ICSBP may have an important role also in human myeloid leukemogenesis.
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PMID:Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. 941 65

The results of the present study demonstrate that cells with the morphologic and phenotypic characteristics of blast cells that are obtained from the peripheral blood of patients with newly-diagnosed or recurrent acute myeloid leukemia (AML) can be stimulated by gamma interferon + lipopolysaccharide (IFN/LPS) to mediate in vitro cytolysis of an NK-insensitive hepatoma cell line. The conditions of IFN/LPS induction and subsequent assessment of cytotoxicity that were employed were identical to those used conventionally to test macrophage-mediated tumor cell cytotoxicity. What was totally unexpected was that these same blast cells, in the absence of stimulation with IFN/LPS, were also found to mediate high levels of spontaneous cytotoxicity against autologous bone marrow cells and against the U937 human promonocytic leukemia cell line in vitro. This high level of spontaneous cytotoxicity against autologous bone marrow or U937 promonocytic leukemia cells was not enhanced by IFN/LPS or MCSF under conditions that stimulated cytotoxic function in normal blood monocytes and was markedly reduced by pretreatment of the blast cells with IL2 under conditions that induced potent NK/LAK-mediated cytotoxicity. Neutralizing antibodies against TNFalpha and/or IL1alpha/beta eliminated the cytolytic function of blast cells against autologous bone marrow or U937 promonocytic leukemia targets. These findings demonstrate the existence of a population of cells with the morphologic characteristics of blast cells in the peripheral blood of AML patients which has the capacity to mediate spontaneous cytolysis of autologous bone marrow cells or a promonocytic leukemia cell line. These cells may be an immature variant of normal precursors produced as a consequence of the disordered hematopoietic environment in the marrow of AML patients. Alternatively, this function may be mediated by a subset of the leukemic blasts themselves.
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PMID:Cytolytic activity of peripheral blood blast cells from patients with acute myeloid leukemia. 947 27

Clinical data and animal models afford evidence for anti-leukemia immunity in humans, but the interactions critical for blast cell recognition are unresolved. Expression of B7 molecules by antigen-presenting cells (APC) provides co-stimulatory signals to T lymphocytes via CD28 and CTLA-4 which prevent the induction of alloantigen-specific tolerance. Conversely, expression of CD40 ligand by stimulated T cells activates APC via CD40. In human hematological B cell malignancies (follicular lymphoma and chronic lymphocytic leukemia), the defect in alloantigen presentation of tumoral cells can be repaired by up-regulation of B7 and other co-stimulatory molecules via CD40. We studied the role of B7 molecules in alloimmune recognition and the various ways to improve the antitumoral response on peripheral blood leukemic cells from 20 patients with a diagnosis of primary acute myeloid leukemia (AML). We focused on myelo/monocytic M4/M5 French-American-British classification subtypes which are considered as the neoplastic counterpart of normal monocytes, a prototypic APC. In one-way mixed lymphocyte reaction of CD4+ T cells against leukemic cells, differences in B7-1, B7-2 or CD40 expression by AML cells did not induce specific cytokine secretion; interleukin (IL)-2 and interferon (IFN)-gamma were detected but not IL-4, corresponding to a Th1 pattern. Blockade experiments showed that proliferation and IFN-gamma secretion only partially depended on B7 molecules, which in contrast had a pivotal role in IL-2 synthesis. In contrast with murine models which suggest a pivotal role for CD80/B7-1 in the immune response against AML, our data support a greater role for CD86/B7-2, in line with the baseline expression of CD86/B7-2 and lack of CD80/B7-1 on most M4/M5 AML cells. AML cell stimulation via CD40: (1) significantly improved IL-2 secretion but not proliferation of responding T lymphocytes, (2) increased CD54/ICAM-1 expression in three quarters of cases, (3) failed in most cases to induce CD40-specific CD80/B7-1 up-regulation, and (4) had a weak effect on CD86/B7-2 expression. These data contrast with the very efficient up-regulation of both B7 co-stimulatory molecule expression and tumoral cell alloimmune recognition following CD40 stimulation in B cell malignancy models. The role of the defective B7 molecule up-regulation by the CD40 pathway in inefficient tumor immunogenicity of primary AML cells has to be further investigated, in particular using transfection experiments of CD80/B7-1-deficient AML cell lines. From our in vitro data we conclude that B7 molecules play an important role in the alloimmune surveillance of AML as suggested by the high B7 molecule dependency of IL-2 secretion. Nonetheless, the contribution of B7 molecules to alloimmune T cell proliferation against primary AML cells in human and the way to improve it--regulation via CD40 in particular--differ from B cell malignancies and murine models, suggesting the requirement for specific strategies in the development of antitumor immunity.
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PMID:Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition. 948 89

Cytokines and growth factors induce activation of the family of signal transducers and activators of transcription (Stats) that directly activate gene expression. Recently, constitutively activated Stat1, Stat3, and Stat5 were identified in nuclear extracts of acute myeloid leukemia (AML) patients, suggesting involvement of constitutive Stat activity in the events of leukemogenesis. In the present study, blasts of nine AML cases were investigated for the constitutive binding activity of the recently identified transcription factor LIL-Stat (LPS- and IL-1-inducible Stat). Band-shift assays were performed using the LPS-and IL-1-responsive element (LILRE) oligonucleotide, a gamma interferon activation site-like site that is present in the human IL-1beta promoter. Constitutive LIL-Stat binding activity was observed in three leukemic cell lines and in seven out of nine AML cases. Transient transfection studies with a reporter plasmid containing three sequential LIL-Stat binding sites showed distinct transcriptional activity of LIL-Stat only in those AML blasts that constitutively expressed LIL-Stat. In CD34+ cells LIL-Stat also constitutively bound to its consensus sequence. However, when these cells were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and stem cell factor (SCF) for differentiation along the monocytic lineage, the LIL-Stat binding activity disappeared totally. In agreement with these findings neither mature monocytes nor granulocytes showed constitutive or inducible LIL-Stat binding activity. We conclude that the LIL-Stat transcription factor is constitutively activated in undifferentiated and leukemic hematopoietic cells, but not in mature cells. This may suggest a role for this transcription factor in the process of differentiation.
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PMID:Differential binding activity of the transcription factor LIL-STAT in immature and differentiated normal and leukemic myeloid cells. 969 25

IL-2 augments the ability of natural killer (NK) cells to kill myeloid leukemia cells in vitro, and may have a role in the eradication of minimal residual disease (MRD) in AML patients. The ability to enhance lysis of AML cells without the toxicity of IL-2 would be a significant improvement in the use of biologics against AML. Recent interest in IL-12 suggested that this cytokine might meet these criteria. The aim of this study was to evaluate the ability of IL-12 to enhance the in vitro lysis of the non-lymphoid leukemia cell lines in a standard 51Chromium release assay. Effector cells from normal volunteers were incubated with varying concentrations of IL-12 or IL-2 for 18-20 h, then the 51Cr-labeled target cells from five different cell lines of AML origin were added for 4 h. Percent lysis was determined and plotted over four effector:target (E:T) ratios. Our results indicated that IL-12 was able to enhance lysis of all cell lines tested at > or =5 units/ml. When IL-2 was added to the culture at a low dose along with IL-12, there appeared to be a synergistic effect. Although anti-gamma interferon was able to inhibit the cytolytic potential of effectors activated by IL-12, the lysis could not be completely blocked. Thus, it appears that IL-12 has the ability to stimulate NK lysis indirectly through the induction of gamma interferon as well as an alternate mechanism not related to gamma interferon. Thus, IL-12 may have a beneficial role in the treatment of non-lymphoid leukemia.
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PMID:Interleukin-12 (IL-12) enhances lysis of non-lymphoid leukemia cell lines in vitro. 969 74

Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.
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PMID:Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse. 1004 23

We report a patient with Philadelphia (Ph)-positive, BCR-ABL rearrangement positive, chronic myeloid leukemia (CML) with a prolonged chronic phase of 24 years who was first prescribed alpha-2 interferon 22 years after initial diagnosis. This therapy was tolerated poorly on account of thrombocytopenia, but an eventual major cytogenetic response was followed soon afterwards by transformation to terminal acute myeloid leukemia (AML). Cytogenetic studies indicated that the transformed myeloblasts were karyotypically normal and Ph negative. Although polymerase chain reaction (PCR) analysis of total leukemic mRNA remained BCR-ABL positive, other molecular studies, including Southern blotting and fluorescent in situ hybridization (FISH) analyses, showed that myeloblasts were BCR-ABL rearrangement negative. PCR-based clonality studies using an X-chromosome-linked restriction fragment polymorphism within the phosphoglycerate kinase gene (PGK1) further showed that the Ph-negative blast cells had a different clonal origin from the Ph-positive clone of chronic phase. We suggest that cases of underlying Ph-negative leukemic transformation in Ph-positive CML warrant further study and should be considered for trial of intensive remission induction therapy as appropriate for acute leukemia.
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PMID:Clonally unrelated BCR-ABL-negative acute myeloblastic leukemia masquerading as blast crisis after busulphan and interferon therapy for BCR-ABL-positive chronic myeloid leukemia. 1004 47

Clinical animal models and in vitro data afford evidence for anti-leukaemia immunity. Many reports have underlined the interest of interleukin-7 (IL-7) use in cancer and its pivotal role in immune recognition. This cytokine, initially identified as a B cell growth factor, enhances the anti-tumour properties of immune effector cells via T lymphocyte activation, increased specific cytotoxicity and cytokine secretion. Nonetheless, few data are available regarding the effect of IL-7 on the expression at the leukaemia cell surface of molecules involved in the immune response, which defective expression could induce tolerance or anergy. This prompted us to study the effects of IL-7 on 20 cases of acute myeloid leukaemia (AML) and 9 cases of lymphoid leukaemia (ALL), in comparison with gamma-interferon, a potent inducer of immune regulation molecule expression. In AML and ALL, IL-7 increased MHC class I molecule expression, while class II molecules were weakly modified. The expression of the tumour necrosis factor family members CD40 and Fas/CD95, together with the adhesion molecules ICAM-1/CD54 and CD58/LFA-3, was also increased in both types of leukaemia. The IL-7 was an efficient inducer of B7-2/CD86 expression in AML and ALL, while increased expression of B7-1/CD80 was only observed in AML. In the corresponding, co-cultured T lymphocyte population, IL-7 more particularly increased B7-1/CD80 and CD58/LFA-3 expression. Finally, pre-incubation of leukaemic cells with IL-7 increased the proliferation of responding, normal allogenic T lymphocytes and their secretion of gamma-IFN and IL-2 in mixed the lymphocyte-tumour reaction. We concluded that IL-7 is efficient at increasing the membrane expression of molecules which are central for the development of the immune response, and at improving allogenic immune recognition. The clinical implications of such data require further in vivo investigation.
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PMID:Differential modulation of immune recognition molecules by interleukin-7 in human acute leukaemias. 1021 Jul 78


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