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

B7 molecules provide an important co-stimulatory signal for T cell receptor/CD3-mediated T cell activation via binding to their cognate receptors, CD28 and CTLA-4. We have introduced B7-1 (CD80) into M1 cells, spontaneously occurring mouse myelocytic leukemic cells, and assessed its potential to induce antitumor immunity to leukemia cells. Syngeneic, immunocompetent SL mice receiving two independent B7-1-transduced monoclonal sublines, M1-B7-1/F/clone F20 and M1-B7-1/F/clone F7, were rejected in 57% and 43% of SL mice, respectively. In vivo depletion of T cell subsets showed that both CD4+ and CD8 T cells were indispensable for the B7-1-dependent anti-leukemic immunity. Although a single exposure of irradiated monoclonal M1-B7/1/F cells was not fully effective, multiple exposures induced protective immunity against subsequent challenge with parental M1 cells. Furthermore, multiple vaccinations with irradiated monoclonal M1-B7-1/F/clone F7 cells could cure 67% of mice previously injected with a lethal number of M1 cells. These results emphasize that multiple exposures of irradiated B7-1-transduced myeloid leukemic cells can induce protective and therapeutic immunity against leukemia and that B7-1-mediated gene therapy may have therapeutic efficacy for patients with acute myelocytic leukemia.
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PMID:Protective and therapeutic immunity against leukemia induced by irradiated B7-1 (CD80)-transduced leukemic cells. 929 32

The number of long-term survivors of patients with acute myeloblastic leukemia (AML) has increased as a result of the progress of chemotherapy. We examined the recovery of peripheral blood lymphocytes (PBL) subset after chemotherapy to clarify the reconstitution of the immune system in AML. Thirty patients with AML in complete remission (CR) were entered into the study. There were 12 males and 18 females; one M0, six M1, 14 M2, three M3, two M4 and four M5 according to FAB classification. The age ranged from 21 to 78 years (median age, 46 years) and the duration of disease-free survival after completion of chemotherapy ranged from 5 to 122 months (median, 35 months). The chemotherapy was performed according to the protocol designed by the Japan Adult Leukemia Study Group (JALSG). PBL subsets were analyzed by flow cytometry with the use of monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD16, CD20, CD45RA, CD56, CD57 and HLA-DR. There was a significant positive relationship between the absolute number of CD4+, CD45RA+ CD4+ cells and the duration of time post-therapy and a significant negative relationship between %CD5+ B, CD56+ cells and the duration of time post-therapy. The appearance of autoantibodies (rheumatoid factor and anti-DNA antibody) tended to increase after 2 years, however, there was no relationship between CD5+ B cells and the frequency of rheumatoid factor. These findings demonstrate that patients in CR have a low number of CD4+ and CD45RA+ CD4+ T cells at an early period after chemotherapy and that each subset recovered to a normal level in 2 years. %CD5+ B and CD56+ cells gradually decreased and returned to their normal level after 4 years. There were high numbers of DR+ T cells and NK cells for a long time, suggesting that activated T cells and NK cells may play a role in the immune surveillance system after chemotherapy.
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PMID:Reconstitution of peripheral blood lymphocyte subsets in the long-term disease-free survivors of patients with acute myeloblastic leukemia. 943 20

Three specific pathogen-free cats experimentally infected with feline immunodeficiency virus (FIV) strains Petaluma, TM1 and TM2, respectively were observed for over 8 years. Without showing any significant clinical signs of immunodeficiency syndrome (AIDS) for 8 years and 4 months of asymptomatic phase, the Petaluma-infected cat exhibited severe stomatitis/gingivitis, anorexia, emaciation, hematological and immunological disorders such as severe anemia, lymphopenia, thrombocytopenia, and decrease of CD4/CD8 ratio to 0.075, and finally died with hemoperitoneum at 8 years and 8 months post-infection. Histopathological studies revealed that the cat had systemic lymphoid atrophy and bone marrow disorders indicating acute myelocytic leukemia (aleukemic type). Plasma viral titer of the cat at AIDS phase was considerably high and anti-FIV antibody titer was slightly low as compared with the other FIV-infected cats. In addition, immunoblotting analysis using serially collected serum/plasma samples of these cats revealed that antibodies against FIV proteins were induced in all the infected cats, however in the Petaluma-infected cat anti-Gag antibodies disappeared during the asymptomatic period. These results suggested that plasma viral load and anti-FIV Gag antibody response correlated with disease progression, and supported FIV-infected cats as a suitable animal model of human AIDS.
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PMID:Eight-year observation and comparative study of specific pathogen-free cats experimentally infected with feline immunodeficiency virus (FIV) subtypes A and B: terminal acquired immunodeficiency syndrome in a cat infected with FIV petaluma strain. 956 Jul 79

Donor-derived CD4+ T cells may play a role in the development of graft-versus-host disease (GVHD) and graft-versus-leukemia reaction after allogeneic bone marrow transplantation (BMT). Therefore, we evaluated the effect of CD4+ T-cell depletion on GVHD and graft-versus-leukemia reaction after HLA-matched BMT. CD4 depletion was performed using anti-CD4 monoclonal antibodies and immunomagnetic beads, initially in small-scale experiments on bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood apheresis products. The result was elimination of the CD4+ T cells from both sources (0% and 2+/-1.4% CD4+ cells, respectively). Subsequently, we used this technique for large-scale negative selection of CD4+ T cells from bone marrow grafts of four consenting leukemic patients in relapse (ALL-3, ANLL-1) (M-3, F-1). The large-scale CD4+ T-cell depletion resulted in >98% (n=4) elimination of CD4+ cells. The resulting population included 17.7+/-4.6% CD3+ T cells, 8.9+/-2.5% CD8+ T cells, 0.1+/-0.1% CD16+ natural killer cells, and 2.3+/-3.2% CD34+ hematopoietic progenitor cells. Patients were transplanted with 2.84+/-1.31 x 10(8) viable cells/kg. They received cyclosporine starting on day -1 as GVHD prophylaxis. Engraftment was fast with a white blood cell count of >1 x 10(9)/L on day 13.2+/-0.5, an absolute neutrophil count of >0.5 x 10(9)/L on day 13.8+/-0.5, and a platelet count of >25 x 10(9)/L on day 26.5+/-6.8. Immunological reconstitution was normal, and peripheral blood phenotyping 3 weeks after BMT disclosed 49.0+/-5.0% CD3, 14.3+/-12.4% CD4, and 59.5+/-7.8% CD8 T cells in addition to 17.0+/-3.0% CD16+ and 9.0+/-3.0% CD56 natural killer cells. Three out of four patients developed very early grade IV GVHD beginning on day 12 (10-13) and died 2-4 months after BMT. One patient is alive and well with a follow-up of 36 months. We conclude that selective CD4 T-cell depletion does not prevent GVHD.
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PMID:Selective CD4+ T-cell depletion does not prevent graft-versus-host disease. 967 38

The c-kit proto-oncogen (CD 117) has been shown to be present in several cell types including normal and neoplastic hemopoietic cells. Among normal BM cells, CD117 expression has been found in about half of the CD34+ precursors including progenitors committed to the erythroid, granulo-monocytic, and megakaryocytic cell lineages. In addition, strong CD117 expression is detected in bone marrow mast cells as well as in a small subset of NK cells displaying strong reactivity for CD56, and in a relatively important proportion of CD3 /CD4 /CD8 prothymocytes. These results suggest that CD117 expression can be detected in both myeloid and lymphoid lineages although for the lymphoid lineage it would be restricted to a small NK-cell subset and early T-cell precursors. In acute leukemias CD117 expression was initially associated with AML. Nevertheless, at present it is well established that CD 117 expression may also be found in a relatively important proportion of T-ALL while it is usually absent in B-lineage ALL. Moreover, recent studies have shown that in about one-third of multiple myeloma cases and patients with monoclonal gammopathy of undetermined significance plasma cells display reactivity for CD1117. The prognostic influence of CD117 expression has not yet been clearly established. The analysis of this marker may also be of value for the investigation of minimal residual disease (MRD). It has been suggested that CD117 in combination with other antigens may be of great help for the identification of leukemia-associated phenotypes that could be used to monitor MRD in both acute myeloid leukemias and multiple myeloma patients achieving morphological complete remission.
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PMID:Expression of the c-kit (CD117) molecule in normal and malignant hematopoiesis. 971 8

Chronic active Epstein-Barr virus (CAEBV) infection has been previously reported to be sometimes associated with an aggressive clinical course. However, the role of EBV in the CAEBV is not well clarified. A retrospective study was performed on nine adult and five child patients (eight males and six females). Histologically, at first admission, the presence of neoplastic lesions could not be confirmed. The lymph nodes in half of all cases revealed paracortical hyperplasia with transformed lymphocytes (hyperplastic type). Half of the cases showed non-suppurative necrosis and an increased number of histiocytes with phagocytosis (histiocytic type). Activated histiocytes with lymphokine positivity were frequently detected in the histiocytic type. In the phenotypical study, 10 of the examined 11 cases showed increased numbers of natural killer (NK) cells and/or CD8-positive T lymphocytes. In situ hybridization (ISH) showed EBV-infected lymphoid cells, but the number of EBV-infected cells varied. Double-labeling immunochemistry/ISH demonstrated EBV-infected T cells, including NK cells, but not B cells. In addition, three cases showed a monoclonal dissemination of EBV terminal repetitive sequence (TR), and two cases showed oligoclonal dissemination. From those findings, monoclonal, oligoclonal and polyclonal populations of EBV-infected T or NK cells were considered to be present in CAEBV states. During the clinical course, 12 of the 14 cases died within 5 years. Six cases died from EBV-associated hematopoietic tumors (histiocytic tumor, T cell lymphoma, B cell lymphoma, plasmacytoma, and NK cell leukemia); one from non-EBV-associated acute myelogenous leukemia, and five due to hemophagocytic syndrome. The examined EBV-associated hematopoietic tumors showed monoclonal EBV terminal repetitive sequences. There is a possibility that the monoclonal dissemination of EBV-infected cells develops from oligoclonal or polyclonal EBV-infected cells. And active histiocytes with lymphokine positivity were frequently detected in the cases with histologically histiocytic type. These findings seem to be related with the causes of death due to hemophagocytic syndrome.
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PMID:Clinicopathological study of severe chronic active Epstein-Barr virus infection that developed in association with lymphoproliferative disorder and/or hemophagocytic syndrome. 995 37

Allogeneic bone marrow transplantation (BMT) is a common treatment of hematologic malignancies. Recurrence of the underlying malignancy is a major cause of treatment failure. Donor-derived cytotoxic T lymphocytes (CTLs) specific for patients' minor histocompatibility antigens (mHags) play an important role in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivities. mHags HA-1 and HA-2 induce HLA-A*0201-restricted CTLs in vivo and are exclusively expressed on hematopoietic cells, including leukemic cells and leukemic precursors, but not on fibroblasts, keratinocytes, or liver cells. The chemical nature of the mHags HA-1 and HA-2 is known. We investigated the feasibility of ex vivo generation of mHag HA-1- and HA-2-specific CTLs from unprimed mHag HA-1- and/or HA-2-negative healthy blood donors. HA-1 and HA-2 synthetic peptide-pulsed dendritic cells (DCs) were used as antigen-presenting cells (APC) to stimulate autologous unprimed CD8(+) T cells. The ex vivo-generated HA-1- and HA-2-specific CTLs efficiently lyse leukemic cells derived from acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) patients. No lytic reactivity was detected against nonhematopoietic cells. Sufficient numbers of the CTLs can be obtained for the adoptive immunotherapy purposes. In conclusion, we present a feasible, novel therapy for the treatment for relapsed leukemia after BMT with a low risk of GVHD.
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PMID:Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. 1063 95

To investigate the clinical implications of germline C mu transcription, the splice region between the 3' end of the enhancer and the first exon of immunoglobulin germline mu; was analyzed by RT-PCR in 63 samples from 59 patients with leukemia. Immunophenotypes of 33 samples from patients with acute leukemia were analyzed using a panel of these monoclonal antibodies: anti-immature/stem cell (HLA-DR, CD34); anti-mature myeloid (CD33, CD15); anti-T lymphoid (CD2, CD3, CD5, CD7, CD8), and anti-B lymphoid (CD10, CD19, CD20). Of the 63 samples, 33 (52%) contained germline C mu transcripts: 2/2 patients with chronic lymphocytic leukemia; 17/26 (65.4%) patients with acute myeloblastic leukemia; all 4 patients with chronic myelogenous leukemia in blast crisis and 1 in accelerated phase; 9/12 patients with acute lymphocytic leukemia. A clear correlation between germline transcripts and HLA-DR expression was observed among germline-positive cases (p < 0. 01). C mu expression and response to therapy clearly indicated that germline-mu-positive leukemia patients responded poorly to chemotherapy and had a worse clinical prognosis compared with C mu-negative patients (p < 0.01). After two courses of chemotherapy, 7/9 C mu-negative patients achieved complete remission compared to only 7/29 C mu-positive patients (p < 0.01). We conclude that the gene-regulating immunoglobulin germline C mu may be amplified in myeloid and B-lymphoid cells during leukemogenesis. Such genetic changes may be correlated with cellular terminal differentiation injury, resistance to chemotherapy and uncontrolled malignant cell proliferation.
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PMID:Transcripts of immunoglobulin germline mu: an amplified myeloid and B-lymphoid common gene program in various leukemias. 1035 29

Expression of the human multidrug resistance 1 gene (MDR1), which encodes the P-glycoprotein transmembrane efflux pump, has been associated with treatment failure of some leukemias, primarily acute myeloid leukemia (AML). To elucidate the epigenetic events associated with overexpression of MDR1 in AML, we analyzed the methylation status of a 2000 bp region within the MDR1 locus using a bisulphite genomic sequencing technique. A CpG-rich domain, approximately 1 kb in size, encompasses the promoter region, exon I, and intron I. This domain was found to be relatively unmethylated in five out of six primary and cultured human hematopoietic cells, as well as five out of six AML patient samples, independent of the MDR1 phenotype. The data suggest that the methylation status of the CpG-rich domain does not act as a 'switch' to regulate expression of the MDR1 gene. In addition, we found an upstream Alu repeat sequence to be unmethylated in three out of five cultured hematopoietic cell lines, both MDR1 expressing and non-expressing. However, analysis of primary CD8-positive T cells and AML patient samples revealed dense methylation of this region which is consistent with methylation of Alu repeat sequences observed in somatic tissues.
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PMID:Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells. 1036 Mar 80

Effective immunotherapy for human leukemia based on infusions of T lymphocytes requires the identification of effector T cells that target the leukemic stem cell. The transplantation of human acute myeloid leukemia into nonobese diabetic/severe combined immune deficient (SCID) mice has identified a rare leukemic progenitor termed the SCID leukemia-initiating cell, which is present in low frequency in the leukemic population and is essential for establishing leukemic hematopoiesis. Thus, this transplant model may be ideally suited to identify effector T cells with antileukemic activity. We report that CD8(+) cytotoxic T lymphocyte (CTL) clones specific for minor histocompatibility antigens inhibit the engraftment of human acute myeloid leukemia cells in nonobese diabetic/SCID mice and demonstrate that this inhibition is mediated by direct CTL recognition of SCID leukemia-initiating cells. These results indicate that CD8(+) minor histocompatibility antigen-specific CTL may be mediators of the graft-versus-leukemia effect associated with allogeneic hematopoietic cell transplantation and provide an experimental model to identify and select T cell clones for immunotherapy to prevent or treat relapse after allogeneic hematopoietic cell transplantation.
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PMID:CD8(+) minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells. 1041 28


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