Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HLA-identical bone marrow transplantation (BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivity. Different T-cell subsets from the bone marrow (BM) graft may be responsible for GVHD and GVL reactivity after BMT. In the etiology of GVHD, not only CD8+ but also CD4+ donor T lymphocytes may play an important role. Here we report a patient with chronic myeloid leukemia (CML) who was transplanted with the BM from his HLA-genotypically identical sister. After BMT there was complete engraftment, but the patient died because of acute GVHD grade III-IV in complete remission. Cytotoxic T-lymphocyte (CTL) lines were generated after BMT using the irradiated leukemic cells from the patient as stimulator cells and the donor-originated peripheral blood mononuclear cells, procured from the patient after BMT, as responder cells. The generated CTL lines showed specific lysis of the recipient lymphocytes and leukemic cells in a 51Cr release assay. Two types of CTL clones could be established from these CTL lines, both phenotypically CD4+. Clone type I showed male-specific HLA-DQ5-restricted lysis of the recipient lymphocytes, but not of the circulating relatively mature leukemic cells from the patient. This may be explained by the low HLA-DQ5 expression of the more mature CML cells. Clone type II showed HLA-DR2-restricted minor histocompatibility antigen-specific lysis of the recipient lymphocytes and leukemic cells. Both types of CTL clones showed antigen-specific cell-mediated growth inhibition of the recipient clonogenic leukemic precursor cells. These CD4+ CTL clones produced several activating cytokines including tumor necrosis factor alpha, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage CSF. Our results illustrate that these CD4+ CTL clones may have induced GVHD directly by cytolysis and indirectly by activating cytokines. Because both types of CTL clones recognized the recipient leukemic progenitor cells, they may also contribute to GVL reactivity after BMT.
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PMID:Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. 767 Jan 18

In the current study, we used a monoclonal antibody-based enzyme-linked immunosorbent assay and bioassay to assess leukemia inhibitory factor (LIF) protein levels, activity, and function in supernatants of 59 adherent layers derived from acute and chronic myelogenous leukemia, myelodysplastic syndrome, and hairy cell leukemia patients and from normal controls. We demonstrate that biologically active LIF protein is constitutively produced and secreted by cultured bone marrow stromal cells from all of the studied subjects. Furthermore, various cytokines can alter endogenous LIF protein levels. Twenty-four h of exposure to recombinant human (rh) interleukin (IL) 4 (100 units/ml) significantly decreased LIF protein levels in adherent layer conditioned media [median base line level, 2.6 ng/ml; range, 1.6-8.0 ng/ml; median post rhIL-4 exposure levels, 1.9 ng/ml; range, 0.9-5.8 ng/ml (n = 7; P = 0.022)]. In contrast, rhIL-1 beta and rh tumor necrosis factor alpha consistently increased LIF protein levels. In the samples exposed to 50 units/ml rhIL-1 beta, median base line LIF level was 2.6 ng/ml; median post-LIF level was 9.0 ng/ml (n = 8; P = 0.014). In the two samples exposed to rh tumor necrosis factor alpha (200 units/ml), LIF levels increased from baseline levels of 2.6 and 2.7 ng/ml to postexposure levels of 7.7 and 12.2 ng/ml, respectively. Finally, the presence of LIF may be relevant to both normal and malignant hematopoietic processes as evidenced by: (a) LIF protein levels in adherent layer conditioned media were significantly elevated in samples from patients with a spectrum of hematological neoplasms [acute myelogenous leukemia: median level, 3.0 ng/ml (range, 1.6-11.0 ng/ml); myelodysplastic syndrome: median level, 4.5 ng/ml (range 1.4-15.5 ng/ml); hairy cell leukemia; median level, 3.5 ng/ml (range 2.2-10.3 ng/ml); chronic myelogenous leukemia-chronic phase: median level, 4.35 ng/ml (range 0.3-19.0 ng/ml); and chronic myelogenous leukemia-blast crisis: median level, 6.25 ng/ml (range 0.7-20.3 ng/ml)] as compared to samples from normal individuals (median level, 2.0 ng/ml; range, 0.7-4.6 ng/ml; P < 0.05); and (b) in normal controls, in vitro abrogation of endogenous LIF bioactivity by neutralizing antibody decreased the number of committed granulocyte-macrophage hemopoietic progenitors.
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PMID:Leukemia inhibitory factor in long-term adherent layer cultures: increased levels of bioactive protein in leukemia and modulation by IL-4, IL-1 beta, and TNF-alpha. 813 98

The clinical correlations of serum tumor necrosis factor alpha (TNF-alpha), a cytokine which can be released from leukemic blasts, has not been extensively studied. We have analyzed serum TNF-alpha in 20 ANLL, one CML-myeloblastic crisis, and 14 ALL adult patients by using a commercial ELISA kit. Sterile serum samples were taken on day 0, day 7, during remission and relapse with a mean follow-up period of 4.2 (1-19) months. After a median of 7 days following chemotherapy, serum TNF-alpha decreased both in responding ANLL (p = 0.004) and ALL (p > 0.05) but remained high in refractory leukemias. Values on day 7 were significantly different between responding and refractory patients in both ANLL (p = 0.0027) and ALL (p = 0.0099). At relapse, serum TNF-alpha increased starting at a median of 3 months preceding clinical symptoms in ANLL (p = 0.002). However, the relapse of ALL coincided with a slight increase which was not significant (p > 0.05). Together these findings indicate that serum TNF-alpha can be used as an early predictor of clinical response and relapse in ANLL.
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PMID:The clinical correlations of serum tumor necrosis factor-alpha in acute leukemias: a predictor of response and relapse? 823 Dec 45

We investigated the ultrastructural effects of recombinant tumor necrosis factor alpha (TNF) on primary leukemia cells of 8 patients (4 cases of acute myelogenous leukemia and 4 cases of chronic myelogenous leukemia) as well as on bone marrow cells of 1 normal control. The cells were kept in liquid culture for up to 92 h in the presence of up to 10,000 U/ml of recombinant human TNF without adding colony-stimulating factors. Under these conditions the concentration of viable leukemic cells decreased by 14 to 53%, compared to control cultures. In acute myelogenous leukemia, all cases to some degree developed an enlargement of mitochondria; in 2 cases prominent cytoplasmic processes, and in 2 cases cytoplasmic vacuoles were observed. In chronic myelogenous leukemia, an enlargement and deformation of all cell types was observed to varying degrees. In the normal bone marrow sample only minor cytoplasmic changes occurred. In all cultures apoptotic changes were rarely observed and--if present--were observed also in cultures without TNF. When the DNA of leukemic cells treated with TNF was separated on agarose, no fragments characteristic of apoptosis were visible. Our results demonstrate that TNF does not induce direct cytotoxicity or apoptosis in acute or chronic myeloid leukemias and are compatible with the notion that some leukemic cells may be activated or stimulated by TNF. The mitochondrion appears to be one of the primary targets of TNF. Electron microscopy is useful for monitoring the changes induced by TNF.
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PMID:Effects of tumor necrosis-factor on primary human leukemia cells: ultrastructural changes. 828 22

The establishment and the biological properties of a new leukemic cell line (KBM-5) derived from a patient in the blastic phase of chronic myelogenous leukemia are described. The cells exhibited multiple copies of the Philadelphia chromosome, and a high level of p210Bcr-Abl kinase activity was detected with rabbit anti-Abl and anti-Bcr (exon 3) peptide antisera. Use of specific primers and polymerase chain reaction followed by Southern blotting revealed that KBM-5 cells carried a bcr3-ABLII splice junction. While a normal BCR message was detected, no normal ABL message was found. The cells were phenotypically myeloid with monocytic differentiation. The high cloning efficiency in semisolid media was independent of the presence of exogenous colony-stimulating factors. In vitro exposure to induces of differentiation, such as retinoic acid, dimethyl sulfoxide, or hemin, failed to influence the growth rate of the cells and their level of differentiation. KBM-5 cells are highly resistant to the antiproliferative action of recombinant alpha- and gamma-interferons. Although sensitive to recombinant tumor necrosis factor alpha, they were completely resistant to natural killer cell action. KBM-5 cells constitutively expressed mRNA for tumor necrosis factor alpha but not for gamma-interferon, other interleukins, or hematopoietic growth factors. The KBM-5 cells that were transplanted into SCID mice manifested metastatic potential and tissue invasiveness similar to the way leukemic cells in humans do. This new KBM-5 cell line represents a helpful model for examining in vitro and in vivo modulation of the growth and properties of leukemic cells by using biological and chemotherapeutic agents.
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PMID:Biological properties and growth in SCID mice of a new myelogenous leukemia cell line (KBM-5) derived from chronic myelogenous leukemia cells in the blastic phase. 833 66

In normal adult mammals, blood cell production, hemopoiesis, takes place within the medullary cavity. There, hemopoietic cell proliferation and differentiation are regulated by a network of stromal/accessory cells and their products (ie cytokines and extracellular matrix molecules), known as the hemopoietic microenvironment. Recent in vitro studies indicate that both cell composition and functional abnormalities of the hemopoletic microenvironment are present in a proportion of patients with myeloid leukemia, both chronic (CML) and acute (AML). Cell composition abnormalities have been primarily observed in a subset of patients with AML; these abnormalities include reduced numbers of fibroblast progenitors and, in some cases, reduced numbers of macrophages and adipocytes. In terms of function, it has been shown that the marrow stromal cells from a significant number of both CML and AML patients, possess a deficient hemopoletic supportive capacity in vitro. This seems to be related to the presence of functionally abnormal, malignant macrophages. The mechanisms by which these macrophages alter the hemopoietic function of the marrow stroma, as a whole, are still not fully understood. Whereas in AML, a macrophage-derived soluble inhibitory activity (containing tumor necrosis factor alpha) has been described; in CML, a direct, macrophage-mediated cell-to-cell contact mechanism for hemopoietic inhibition seems to be involved. To date, however, it is not clear whether the abnormalities in the hemopoietic microenvironment are secondary to myeloid leukemia or if they precede clinical CML/AML. Furthermore, it is not known to what extent the functional abnormalities observed in vitro contribute to the hematologic dysfunction that characterizes myeloid leukemia and to the in vivo progression of the disease.
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PMID:Composition and function of the hemopoietic microenvironment in human myeloid leukemia. 866 39

The objective of the present study was to investigate the interactions of 2-chlorodeoxyadenosine (2-CdA) with interferon alpha or gamma (IFN-alpha, IFN-gamma), as well as between 2-CdA and recombinant human tumor necrosis factor alpha (rhTNF-alpha), on the clonal growth of granulocyte-macrophage progenitor cells (CFU-GM) from patients with chronic myeloid leukemia (CML) and on clonogenic leukemia blasts (CFU-L) from acute myeloid leukemia (AML) patients. Progenitor cell culture in semisolid medium in vitro was applied and the percentage of colony growth inhibition was evaluated. The use of 2-CdA either with IFN-alpha or IFN-gamma and 2-CdA with TNF-alpha was found to inhibit, in a dose dependent manner, the growth of colonies formed by hematopoietic precursor cells from CML and AML patients as well as from normal individuals, with the greatest effect being observed after the use of 2-CdA and IFN-alpha at their highest concentrations.
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PMID:Interaction of 2-chlorodeoxyadenosine in combination either with interferons or recombinant human tumor necrosis factor alpha on myeloid progenitor cells in vitro. 901 67

CD34(+) hematopoietic stem cells from normal individuals and from patients with chronic myelogenous leukemia can be induced to differentiate into dendritic cells (DC). The aim of the current study was to determine whether acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells could be induced to differentiate into DC. CD34(+) AML-M2 cells with chromosome 7 monosomy were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFalpha), and interleukin-4 (IL-4). After 3 weeks of culture, 35% of the AML-M2 cells showed DC morphology and phenotype. The DC phenotype was defined as upmodulation of the costimulatory molecules CD80 and CD86 and the expression of CD1a or CD83. The leukemic nature of the DC was validated by detection of chromosome 7 monosomy in sorted DC populations by fluorescence in situ hybridization (FISH). CD34(+) leukemic cells from 2 B-ALL patients with the Philadelphia chromosome were similarly cultured, but in the presence of CD40-ligand and IL-4. After 4 days of culture, more than 58% of the ALL cells showed DC morphology and phenotype. The leukemic nature of the DC was validated by detection of the bcr-abl fusion gene in sorted DC populations by FISH. In functional studies, the leukemic DC were highly superior to the parental leukemic blasts for inducing allogeneic T-cell responses. Thus, CD34(+) AML and ALL cells can be induced to differentiate into leukemic DC with morphologic, phenotypic, and functional similarities to normal DC.
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PMID:CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells. 1047 34

Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. In a murine retroviral bone marrow transduction-transplantation model, a Tel (exon 1-5)-Abl fusion protein induced 2 distinct illnesses: a CML-like myeloproliferative disease very similar to that induced by Bcr-Abl but with increased latency and a novel syndrome characterized by small-bowel myeloid cell infiltration and necrosis, increased circulating endotoxin and tumor necrosis factor alpha levels, and fulminant hepatic and renal failure. Induction of both diseases required the Tel pointed homology oligomerization domain and Abl tyrosine kinase activity. Myeloid cells from mice with both diseases expressed Tel-Abl protein. CML-like disease induced by Tel-Abl and Bcr-Abl was polyclonal and originated from cells with multilineage (myeloid, erythroid, and B- and T-lymphoid) repopulating ability and the capacity to generate day-12 spleen colonies in secondary transplantations. In contrast to findings with Bcr-Abl, however, neither Tel-Abl-induced disease could be adoptively transferred to irradiated secondary recipient syngeneic mice. These results show that Tel-Abl has leukemogenic properties from distinct from those of Bcr-Abl and may act in a different bone marrow progenitor.
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PMID:The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice. 1203 90

Natural killer (NK) cells decrease in function during chronic myelogenous leukemia (CML) progression from chronic phase to blast crisis, and they can become BCR/ABL(+) late in the disease course. To study this altered function, NK92 cells were transduced with the BCR/ABL oncogene. In contrast to the parental cells, which died when deprived of interleukin 2 (IL-2), p210(+) NK92 cells proliferated and survived indefinitely in the absence of IL-2. BCR/ABL also decreased the natural cytotoxicity of NK92 cells against K562 targets, without affecting IL-2, interferon gamma (IFN-gamma), or tumor necrosis factor alpha (TNF-alpha) production. Although the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI-571) had no effect on parental NK92 cells, it markedly decreased the growth and survival of IL-2-independent p210(+) NK92 cells. In contrast to the parental cell line, serial analysis of p210(+) NK92 cells detected small populations that clonally expressed one or more killer immunoglobulin-like receptors (KIRs). Unlike the decreased natural cytotoxicity, the function of the activating CD158j receptor remained intact. Southern blotting and hybridization with an enhanced green fluorescence protein (eGFP) probe showed that KIR(-) and KIR(+) NK92 cells were all derived from the same clone, suggesting that KIR acquisition remains dynamic at the maturational stage represented by the NK92 cell line. When tested in primary CD56(+bright) NK cells, p210 induced partial IL-2-independent growth and increased KIR expression similar to findings in NK92 cells. This is the first study to show that BCR/ABL, well known for its effects on the myeloid lineage, can alter the function of lymphoid cells, which may be associated with the defect in innate immunity associated with CML progression.
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PMID:BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs). 1251 22


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