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 nature of the spontaneous expression of cytokines that is observed in blasts of some AML patients is unclear. We studied whether or not the spontaneous expression of IL-1 beta and IL-6 is due to an increased transcription rate of the cytokine gene and associated with a spontaneous expression of two transcription factors that play an important role in IL-1 beta and IL-6 gene transcription, namely activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B). In eight of the 19 AML patients a spontaneous expression of IL-1 beta mRNA was observed, whereas IL-6 mRNA was expressed in seven of the cases. Expression of IL-6 mRNA correlated nicely with the secretion of IL-6 protein. Nuclear run-on experiments showed that spontaneous expression of IL-1 beta and IL-6 was at least partly due to an increased transcription rate of the respective genes compared to the results from healthy unstimulated monocytes. Electrophoretic mobility shift assays demonstrated that especially spontaneous expression of NF-kappa B is associated with spontaneous cytokine expression. However, the spontaneous expression of transcription factors is not due to the endogenous secretion of IL-1 since the addition of anti-IL-1 monoclonal antibody did not affect the expression of NF-kappa B. Finally, supershift experiments were performed that demonstrated that the NF-kappa B consists of the p50 and the p65 subunits. In summary, these results demonstrate that the spontaneous expression of cytokines is frequently associated with an increased transcription rate and a spontaneous expression of transcription factors.
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PMID:The spontaneous expression of interleukin-1 beta and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kappa B transcription factor in acute myeloblastic leukemia cells. 788 41

Although many associations have been found between specific HLA antigens and an increased susceptibility to various diseases, previous attempts to associate class I and II antigens with acute myeloid leukemia (AML) have been inconclusive, probably due in part to the heterogeneity of AML. We subdivided 165 consecutive adults with AML de novo into distinct clinical, morphological, and cytogenetic subsets and then tested for statistically significant associations with specific HLA antigens. Both morphology and cytogenetic pattern identified subsets of patients with important clinical features and different outcomes. Ten statistically significant (P < 0.05) HLA cytogenetic associations were observed: HLA-A11 with t(8;21), A26 with t(15;17), B7 with 11q23 abnormalities, B44 with +8, Cw2 with -20/del(20q), DR3 with t(15;17) and FAB-M3, DR4 with inv(16) and FAB-M4Eo, DQ2 with +8, and DQ6 with +22. HLA-DQ1 had a negative association with -5/del(5q), which was present in 13% of the 165 AML patients overall but in none of the 27 with DQ1. Certain HLA antigens were significantly correlated with more favorable remission rates, remission duration and survival. Possible mechanisms for the association of HLA antigens with particular subtypes of AML include the linkage or co-inheritance of an oncogene, the facilitation of binding of a transforming virus, toxin, or cytokine, or a permissive role involving impaired immune recognition of an emerging neoplasm. Given the heterogeneity of both the HLA system of immune recognition genes and the cytogenetic subtypes of AML, however, larger numbers of patients must be studied to have confidence that biologically important relationships truly exist.
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PMID:Certain HLA antigens are associated with specific morphologic and cytogenetic subsets of acute myeloid leukemia. 788 42

The complication of secondary myelodysplastic syndrome (sMDS) during the course of multiple myeloma (MM) has been recognized for more than a decade. sMDS occurs years after MM diagnosis, and typically, at sMDS presentation the MM is stable or inactive. We report a 56-year-old patient, who developed sMDS 15 years following the diagnosis of IgG-lambda MM, which had been completely stable for 13 years. However, very soon after sMDS was diagnosed, the MM relapsed and required combination chemotherapy. The first cycle of vincristine, adriamycin and dexamethasone (VAD) resulted in severe neutropenia and sepsis, which was treated with antibiotics and recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). Two weeks after GM-CSF administration a transformation to acute myeloblastic leukemia was observed. The relation between GM-CSF and the leukemic transformation is discussed and the possible contribution of the cytokine to the stimulation of this complication is emphasized.
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PMID:Is granulocyte-macrophage colony-stimulating factor (GM-CSF) safe in myelodysplastic syndromes? 789 Feb 61

Myeloblasts derived from the peripheral blood of a patient with acute myelogenous leukemia (ORL47) were found to represent the malignant counterpart of the newly elucidated monocyte-dendritic cell colony-forming unit (mono-DC-CFU). The specific cytokine conditions require to achieve intermediate and terminal maturation of DCs and monocytes from these progenitors were defined. With tumor necrosis factor (TNF) + granulocyte-macrophage colony-stimulating factor (GM-CSF) + stem cell factor treatment numerous colony-like clusters developed. In contrast with normal DC development, further advancement of mono-DC-CFU and terminal DC maturation from the leukemic cells were dependent on the addition of interleukin-6. Functional and phenotypic analysis showed that the capacity to differentiate was maintained fully in the DC compartment, but only partially in the monocyte compartment, as judged by the lack of CD14 surface expression. Cells found at intermediate stages of DC development were potent stimulators of a mixed leukocyte reaction, a function usually attributed to mature DCs. As previously shown for normal DC development, antibodies to TNF alpha and GM-CSF blocked proliferative responses and DC growth. The importance of these observations in the classification of leukemias, normal DC development, and potential clinical strategies is discussed.
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PMID:Identification of a malignant counterpart of the monocyte-dendritic cell progenitor in an acute myeloid leukemia. 794 77

Various types of cytokines have been used in in vitro experiments to generate cytokine-induced killer (CIK) cells that are reactive to patient acute myeloid leukemia (AML) cells. Of these CIK cells, interleukin-2 (IL-2)-activated peripheral blood mononuclear cells, i.e., lymphokine-activated killer (LAK) cells, with the initial addition of the anti-CD3 monoclonal antibody (T3 LAK cells), are the most potent cytotoxic lymphocytes, and have marked proliferative capacity. The cytotoxicity of such T3 LAK cells against CD13+ AML cells is further enhanced by the addition of anti-CD3 x anti-CD13 bispecific antibody (BsAb) during the cytotoxicity assay. The combined use of T3 LAK cells and the BsAb can be used for ex vivo purging of CD13+ AML cells in autologous bone marrow transplantation. Other cytokines, such as IL-7 or IL-7 in combination with IL-2, or newly identified cytokines, will also be tested in attempts to obtain more specific and more potent effector cells. Studies of methods to increase the susceptibility of AML cells to CIK are also required.
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PMID:Cytotoxicity of cytokine-induced killer cells coated with bispecific antibody against acute myeloid leukemia cells. 795 Sep 10

Blast cells from up to 70% of patients with acute myeloblastic leukemia (AML) exhibit a variable degree of autonomous growth in vitro which is related to the production of autocrine growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Approximately 40% of AML blasts with autonomous growth have been reported to exhibit abnormalities of retinoblastoma (Rb) protein expression. As the Rb protein is a known transcriptional repressor of the IL-6 promoter, we have investigated the relationship between absence of Rb protein and cytokine gene expression in AML. Blasts from 28 patients were studied, 19 were Rb protein positive by Western blot and by flow cytometry for nuclear Rb protein; blasts from nine patients were Rb-negative. Of the 28 specimens tested by RT-PCR, 24 were positive for GM-CSF mRNA, 21 for IL-1 beta mRNA, and 14 for IL-6 mRNA. Only the expression of IL-6 was found to be significantly associated with loss of Rb protein expression (p < 0.02). The relationship between Rb protein and IL-6 expression was further studied by suppressing Rb protein expression with antisense oligonucleotides. In three out of seven blasts so treated, IL-6 mRNA was induced following antisense treatment whereas control sense oligonucleotides had no effect. Blasts from four patients which secreted high levels of IL-6 exhibited in vitro autonomous growth which could be partially suppressed by anti-IL-6. These results suggest that deletion of Rb protein expression is a mechanism that can dysregulate IL-6 expression in leukemic blasts and thus potentiate the autonomous growth of these cells.
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PMID:Absence of retinoblastoma protein expression results in autocrine production of interleukin-6 and promotes the autonomous growth of acute myeloid leukemia blast cells. 796 42

Carboplatin is an analogue of cisplatin, an agent that has found application in the cancers that afflict more than one half of children with malignancy. Exploration of the potential of cisplatin has been impeded by its severe and persistent ototoxicity and nephrotoxicity and its prolonged emetogenicity. At conventional doses, carboplatin appears to have a similar spectrum of activity. Its toxicity profile is limited largely to myelosuppression, which may be predicted with some precision from drug dose and glomerular filtration rate, and can be ameliorated with cytokine or bone marrow rescue. Cisplatin nephrotoxicity and especially ototoxicity have been less amenable to amelioration. Unlike cisplatin, carboplatin has demonstrated activity in adult acute myeloblastic leukemia. Exploration of carboplatin proceeds in the setting of bone marrow or cytokine rescue, in combination with nephrotoxic drugs like ifosfamide, in children with brain tumors who are especially susceptible to ototoxicity and in children with acute leukemia.
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PMID:Carboplatin in pediatric malignancies. 799 69

Retinoic acids (RAs) exert pleiotropic effects on cellular growth and differentiation. All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA), a stereoisomer of ATRA, induce differentiation of leukemic cell lines and cells from patients with acute myelogenous leukemia (AML) in vitro. Despite information on the effects of RAs on hematopoietic cells, little is known about how RAs act on the hematopoietic microenvironment, especially on bone marrow stromal cells. Based on recent observations that various cytokines produced mainly by bone marrow stromal cells regulate hematopoiesis, we analyzed the effects of RAs on cytokine production by these cells. ATRA or 9-cis RA treatment of human bone marrow stromal cell line KM101, which produces macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) constitutively, enhanced mRNA levels of both cytokines in a dose-dependent manner. Both RAs also stimulated M-CSF production from primary cultures of human bone marrow stromal cells. Both retinoic acid receptor (RAR)-alpha and retinoid X receptor (RXR)-alpha were expressed constitutively in KM101 cells. ATRA did not affect the expression of either receptor, whereas 9-cis RA increased RXR-alpha mRNA expression in a dose-dependent manner, but did not affect levels of RAR-alpha mRNA. These findings may have important biologic implications for both the role of RAs in hematopoiesis and the therapeutic effects of ATRA on the hematopoietic microenvironment in patients with acute promyelocytic leukemia (APL).
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PMID:Retinoids (all-trans and 9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by human bone marrow stromal cells. 799 28

Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.
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PMID:Childhood acute myeloid leukemia in mice with severe combined immunodeficiency. 801 18

Campath-1 (CDw52) antibodies (IgM and IgG2b) have been used in vitro and in vivo for control of GVHD and prevention of rejection following bone marrow transplantation. Results of 951 patients with malignant disease transplanted from HLA-matched siblings are reported. Both Campath-1M and Campath-1G are shown to be effective when used in vitro for prevention of graft-versus-host disease (GVHD). Graft failure was reduced by addition of cyclosporin A (CsA) post-transplant and possibly also by total lymphoid irradiation (TLI) pre-transplant. However, treatment of the recipient with Campath-1G to deplete residual lymphocytes was more effective, reducing the incidence of graft failure from 21% to 9% (in the absence of CsA). GVHD was virtually eliminated and leukaemia-free survival was improved. However, the risk of relapse was increased by T cell depletion, certainly in CML and to a lesser extent in AML. Addition of donor T cells to the depleted bone marrow or early post-transplant restored the risks of GVHD, graft failure and relapse to much the same as without T cell depletion. One problem associated with the use of Campath-1G in vivo was a significant delay (by up to 7 days) in neutrophil engraftment. This was unlikely to be caused by toxicity to progenitor cells and we argue that small numbers of lymphocytes may be required to assist early engraftment, possibly by cytokine production. If this problem can be overcome, T cell depletion of donor and recipient may be a good alternative to conventional GVHD prophylaxis for matched sibling transplants, resulting in a superior quality of life for the survivors. It is also likely to be particularly beneficial in transplants for non-malignant diseases and transplants from unrelated donors.
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PMID:Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases. 777 29


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