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)

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

Despite sufficient levels of HLA class I and class II expression, acute myeloid leukemia (AML) cells usually fail to induce a significant T-cell response in vitro. Therefore, we investigated whether in vitro modifications could enhance the T-cell stimulatory properties of AML cells. AML cells were either cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-alpha), or transfected with the CD80 (B7.1) gene and used as stimulator cells for primed and unprimed allogeneic T cells. Cytokine treatment increased HLA class I and II expression, but did not induce CD80 on AML cells. Cytokine-treated AML cells efficiently presented nominal and allo-antigens to primed T-cell clones, induced strong T-cell proliferation in HLA mismatched mixed lymphocyte reactions (MLR), but failed to induce primary T-cell responses from an HLA identical bone marrow donor in MLR. In contrast, CD80-transfected AML cells induced T-cell proliferation of HLA-identical bone marrow donor peripheral blood mononuclear cell (PBMC) in primary MLR, allowing the generation of leukemia reactive CD4(+) T-cell lines and clones. The majority of the generated oligoclonal (25 of 35) T-cell cultures showed patient specific reactivity that did not discriminate between patient's leukemic cells and Epstein-Barr virus (EBV)-transformed B cells (EBV-LCL). The remaining 10 oligoclonal T-cell cultures recognized only leukemic cells. One of these latter leukemia reactive oligoclonal T cells was cloned. The majority of the clones (25 of 29) reacted against both leukemic cells and patient's EBV-LCL. A minority of the T-cell clones with the CD4 phenotype (four of 29) showed strong HLA-DP restricted reactivity against leukemic cells, but not against patient's EBV-LCL or against HLA-matched nonleukemic cells, indicating that their target antigens are preferentially expressed by leukemic cells. In conclusion, our study shows that the in vitro allogeneic T-cell response induced by CD80-transfected AML cells is mainly directed against patient's specific minor histocompatibility antigens, while antigens preferentially expressed by leukemic cells can also trigger T-cell responses.
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PMID:CD80-Transfected acute myeloid leukemia cells induce primary allogeneic T-cell responses directed at patient specific minor histocompatibility antigens and leukemia-associated antigens. 971 96

Although hematologic dysplasia is common in HIV disease, evolution to AML is unusual. We report a case of AML in a patient with stage-C3 AIDS who had been previously treated with granulocyte colony-stimulating factor (G-CSF). This 41-year-old black man presented with pancytopenia (Hg 8.6 g/dl, Hct 24.3%, platelets 16,000/mm3, WBC 0.6 x 10(3)/mm3) and hemoptysis. His peripheral smear manifested 19% blasts. His bone marrow biopsy was hypocellular (20%) with greater than 90% blasts, which were positive for myeloperoxidase and Sudan black B. The blasts were negative for nonspecific esterase. Immunophenotypic analysis by flow cytometry showed the majority of cells to be of myeloid lineage, expressing CD13, and CD45 at low intensity. In addition, there was aberrant expression of CD2 and no expression of CD14 or CD4. The diagnosis of AML-FAB-M1 was made. The patient refused chemotherapy. Of the rare cases of AML in HIV patients previously reported in the literature, the majority were of the monocytic or myelomonocytic subtype. This case is of special interest because of prior G-CSF therapy. In this setting, the relationship between HIV, G-CSF, and subsequent AML is controversial.
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PMID:Acute myelogenous leukemia (FAB AML-M1) in the setting of HIV infection and G-CSF therapy: a case report and review of the literature. 976 Jan 57

The mechanism underlying the cytotoxicity mediated by a human CD4(+) cytotoxic T-lymphocyte (CTL) clone directed against a peptide derived from the acute myelogenous leukemia-associated fusion protein, DEK-CAN, was investigated. A DEK-CAN fusion peptide-specific CD4(+) Th0 CTL clone, designated HO-1, was established from the peripheral blood lymphocytes of a healthy individual. HO-1 exerted direct but not "innocent bystander" cytotoxicity within 2 hours. The cytotoxicity mediated by HO-1 was completely Ca2+-dependent. Because HO-1 lysed peptide-loaded Fas-deficient target cells derived from a patient with a homozygous Fas gene mutation, its cytotoxicity appeared to be mediated by a Fas-independent pathway. In addition, its cytotoxicity was only partially inhibited by treatment with concanamycin A and strontium ions, which are inhibitors of the perforin-based cytotoxic pathway. Although membrane-bound type of tumor necrosis factor-alpha (TNF-alpha) was expressed on HO-1, an anti-TNF-alpha antibody had no effect on HO-1-mediated cytotoxicity. HO-1 expressed mRNA for apoptosis-inducing mediators, including perforin, granzyme B, Fas ligand, TNF-alpha, and lymphotoxin; however, no DNA fragmentation was detected in target cells incubated with HO-1 by 5-[125I]Iodo-2'-deoxyuridine release assay and agarose gel electrophoresis of DNA. Although it has been suggested that the Fas/Fas ligand system is the main pathway by which CD4(+) CTL-mediated cytotoxicity is exerted in murine systems, HO-1 produced peptide-specific and HLA-restricted cytotoxicity via a Fas-independent and nonapoptotic pathway. The present study thus describes a novel mechanism of cytotoxicity mediated by CD4(+) CTL.
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PMID:Fas-independent and nonapoptotic cytotoxicity mediated by a human CD4(+) T-cell clone directed against an acute myelogenous leukemia-associated DEK-CAN fusion peptide. 992 Aug 42

This study reports findings from a retrospective, comprehensive review of 80 cases of adult AML in regard to cytomorphology, enzyme cytochemistry (EC), flow cytometric immunophenotyping (FCI), and chromosomal analysis. From this review, we conclude that diagnostically challenging cases can only be subtyped by combining the cytomorphology with EC, FCI, and subsequent cytogenetic results. This is particularly true in recognizing the hypogranular variant of AML,M3 (AML, M3m) and distinguishing it from other subtypes. Nonlineage expression of markers (CD1, CD2, CD4, CD5, CD7, and CD56) was nonspecific as to AML subtype. Of interest, CD2 coexpression in acute myelomonocytic leukemia with eosinophilia (M4-Eo) was exclusively associated with inversion of chromosome 16 (inv 16) and was not observed in the other M4-Eo's without inv16. We also recognized a previously undescribed M3m with CD56 coexpression, heightening awareness of this entity which needs to be distinguished from the unique subtype of CD56+ AML with otherwise similar immunophenotypic and morphologic characteristics. In addition, nonlineage expression of CD19 alone was exclusively associated with the cytogenetic finding of t (8;21) (q22; q22) and thus may represent a favorable prognostic indicator by FCI.
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PMID:Comprehensive review of adult acute myelogenous leukemia: cytomorphological, enzyme cytochemical, flow cytometric immunophenotypic, and cytogenetic findings. 1002 33

Malignant hematolymphoid disorders arising from natural killer (NK) cells have become widely recognized in the past decade. Recently, we as well as others have drawn attention to some neoplasms of conceivable NK cell precursor origin that might represent two distinct entities, i.e. myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia. Both of these diseases were characterized by remarkable extramedullary involvement and lymphoblastoid morphology, although the sites of involvement differed. Myeloid/NK cell precursor acute leukemia exhibited more frequent involvement of bone marrow (BM) and lymph nodes, whereas blastic NK cell lymphoma/leukemia affected extranodal sites, mainly the skin/subcutis. Tumor cells of these two diseases shared the CD16-, CD56+ and CD57- phenotype, but differed in other phenotypic profiles. Indeed, myeloid/NK cell precursor acute leukemia was immunophenotypically characterized by the expression of CD34 and blastic NK cell lymphoma/leukemia by that of CD4. On the theoretical level in the NK cell differentiation pathway, myeloid/NK cell precursor acute leukemia might be derived from a myeloid antigen-positive precursor preceding a NK cell committed precursor as a conceivable counterpart of blastic NK cell lymphoma/leukemia. Most cases with either disease lacked cytotoxic activities or molecules, a finding which seems to support their precursor origin. Notably, Epstein Barr virus (EBV) was negative in all cases, which contrasted with its high level associated with mature NK cell malignancies. Chemotherapy for acute myeloid leukemia was generally effective for myeloid/NK cell precursor acute leukemia, while the regimen for lymphoid malignancy was effective for blastic NK cell lymphoma/leukemia. These data suggests that each of these two diseases constitutes a distinct entity, which is also different from mature NK cell malignancies.
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PMID:Malignancies of natural killer (NK) cell precursor: myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia. 1090 10

An immune response is involved in the control of leukemias as demonstrated by allogeneic bone marrow transplantation, by the eradication of residual leukemic cells by cytotoxic T cells and finally by the identification of tumor antigens which are recognized by effector T cells. Dendritic cells (DC) are professional antigen-presenting cells (APC) able to present antigens in the context of co-stimulatory signals necessary for T cell activation. Although tumor cells may express tumor antigens, they are usually unable to elicit an immune response since they are devoid of co-stimulatory capacities. To overcome this problem, engineering tumors to provide APC function could potentially result in polyvalent immunization to multiple tumor antigens. We have tested the differentiation of AML-5 (monoblastic, promonocytic and monocytic) leukemia cells and demonstrated that eight out of the ten fresh human acute myeloid leukemia populations tested can differentiate in vitro into bona fide APC. Leukemic cells acquire in vitro DC morphology, mature DC markers such as CD83, the up-regulation of MHC and co-stimulatory molecules and the ability to produce IL-12 upon maturation, while retaining their characteristic caryotypic abnormalities. However, we could not obtain an immature DC phenotype. They also acquire the ability to induce the differentiation of allogeneic naive cord blood CD4 and CD8 T cells as well as resting autologous cytotoxic T cells. These results demonstrate that some tumor cells acquire APC phenotype and functions and can thereby induce a potent autologous immune response that will be a valuable tool for detection of new tumor antigens and for in vivo immunization.
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PMID:Human acute myeloblastic leukemia cells differentiate in vitro into mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias. 1045 72

We investigated early immunological reconstitution and the production of circulating inflammatory mediators and their relationship to aGVHD in children during the first 100 days following unrelated UCBT. Nine patients had an underlying malignant disease (ALL, ANLL), and two, non-malignant diseases (SAA, ALD). The median age was 10 years (range: 1.25-21). Seven of 11 patients were alive by day 100, two died from regimen-related toxicity, and two died from severe aGVHD (grade >/=III). Myeloid engraftment (ANC >/=500/mm3 x 2 days) occurred at a median of 24 days (range: 14-55), while platelet engraftment (platelet count >/=20 000/mm3 untransfused x 7 days) was delayed and occurred at a median of 52 days (range: 33-95). The mean cell dose of CD34+ cells was 3.3 +/- 3.51 x 10(5)/kg, and of CD34+/CD41+ cells was 3.94 +/- 3.99 x 10(4)/kg. Acute GVHD (grade II-IV) developed in seven patients (77%), and severe aGVHD (grade III-IV) developed in five patients (55%). Serum levels of IL-2Ralpha, IL-2, IL-4, IL-7, IL-12, and IFNgamma were not significantly different between patients with grades 0-I aGVHD and patients with grades II-IV aGVHD. Evaluation of immunological reconstitution on day 90 post UCBT demonstrated an early recovery of the absolute numbers of B cells (CD19+) and NK cells (CD3-/CD56+). Immunoglobulin levels for IgG, IgM and IgA remained normal throughout the study period. PMN functional studies demonstrated normal superoxide generation, bacterial killing (BK), and chemotaxis (CTX). However, both helper (CD3+/CD4+) and suppressor (CD3+/CD8+) T cell subsets remained low during the first 100 days post UCBT with mean +/- s.e.m. values of 120 +/- 29/mm3 and 10 +/- 50/mm3, respectively (normal = 900-2860/mm3 (CD3/CD4), normal = 630-1910/mm3 (CD3/CD8)). Mitogen response studies showed low blastogenesis to PHA and PWM, with a mean c.p.m. +/- s.e.m. value of 1.7 +/- 0.67 x 10(4) for PHA (NL >/= 75 x 10(3)) and 8.42 +/- 4.1 x 10(3) for PWM (NL >/=25 x 10(3)). In conclusion, serum levels of inflammatory mediators were not predictive nor did they correlate with the severity of aGVHD. Recovery of NK cells, B cells, and PMN functions occurred within the first 90 days post transplant. However, T cell subsets, CD3+/CD4+ and CD3+/CD8+, and T cell functional activity remained significantly decreased and may account for the high incidence of infectious morbidity seen during this immediate post UCBT period.
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PMID:Immunological reconstitution and correlation of circulating serum inflammatory mediators/cytokines with the incidence of acute graft-versus-host disease during the first 100 days following unrelated umbilical cord blood transplantation. 1048 39

We have established a T lymphoid cell line, K2-MDS, from the peripheral blood mononuclear cells (PBMC) of a patient with acute myeloblastic leukemia (AML) transformed myelodysplastic syndrome (MDS). K2-MDS cells are positive for the expression of CD4, CD5, CD13, CD25, CD71, CD95, HLA-DR and cytoplasmic CD3. Southern blotting analysis shows T cell receptor (TCR) beta chain genes rearrangements, whereas immunoglobulin heavy chain (IgH) genes are not rearranged. Further, the patient PBMC contains TCR beta chain genes rearrangements in the same manner as K2-MDS cells. The data indicate that K2-MDS is a T lymphoid cell line derived from a myelodysplastic clone in the patient PBMC. This new MDS-derived cell line K2-MDS may be a useful in vitro model for studies on the pathogenetic mechanisms leading to MDS.
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PMID:Establishment of a myelodysplastic syndrome (MDS)/secondary AML-derived T lymphoid cell line K2-MDS. 1065 44


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