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

The success of adoptive immunotherapy for the treatment of leukemia depends on the generation of T cells that can specifically react with malignant cells. Dendritic cells (DCs) are important antigen-presenting cells in the development of antileukemic T-cell responses. In this study, we generated DCs from peripheral blood cells of patients with chronic myelogenous leukemia (CML). CML cells incubated concurrently with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha in vitro developed morphologic and phenotypic characteristics of DCs. Fluorescence in situ hybridization showed the presence of t(9;22) in the nuclei of these cells, indicating that they were leukemic in origin. These cells were potent stimulators of lymphocyte proliferation in specific in vitro assays for DC function. Autologous T cells stimulated with in vitro-generated, leukemic DCs displayed vigorous cytotoxic activity against CML cells but low reactivity to major histocompatability complex-matched normal bone marrow cells. Cytotoxic activity against CML targets was fourfold to sixfold higher using DC-stimulated autologous T cells than with autologous T cells expanded by culture with interleukin-2 alone. DC-stimulated T cells also inhibited growth of CML clonogenic precursors in colony-forming assays in vitro. These results suggest that cytokine-driven in vitro differentiation of CML cells results in generation of DCs with potent T-cell stimulatory function. In vitro-generated DCs can be effectively used as antigen-presenting cells for the ex vivo expansion of antileukemic T cells.
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PMID:Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia. 902 34

We investigated the role of endogenous or exogenous nitric oxide (NO) on human lymphocyte function. We used sodium nitroprusside, nitroglycerine, S-nitroso-N-acetylpenicillamine, sodium nitrite and S-nitroso-L-glutathione as NO-generating compounds. All agents were used at doses that do not produce direct cytotoxicity as measured by trypan blue exclusion as well as chromium-51 release assay. The immune responses examined were peripheral blood lymphocytes (PBL) proliferation and IL-2 production after activation with OKT3 and PHA; allogeneic mediated proliferation and cell mediated cytotoxicity (CML) in MLR; IgG and IgM production after PBL activation with Con-A; proliferation and expression of IFN-gamma and IL-4 mRNA after activation of allogeneic CD4+T cell clones. Cytokine mRNA expression was measured by reverse transcriptase PCR. Our results show that proliferating lymphocytes do not produce a detectable amount of NO as measured by the Griess reaction. In separate experiments, the addition of NG-monomethyl-L-arginine (L-NMMA) did not affect lymphocyte proliferation. Sodium nitroprusside and nitroglycerine exerted a dose dependent antimitogenic effect, inhibited cytokine production and expression, CML generation and antibody production. DNA gel electrophoresis showed no evidence for enhanced programmed cell death. The antimitogenic effect could not be blocked by the NO scavengers, hemoglobin or methylene blue. In contrast, the other nitric oxide generating compounds did not inhibit lymphocyte mitogenesis. The results suggest that human lymphocytes do not produce appreciable amounts of NO to affect lymphocyte mitogenesis. Sodium nitroprusside and nitroglycerine have a potent but nonspecific immunoinhibitory effect on human lymphocyte function by a mechanism other than NO production. In addition, pharmacological levels of NO do not inhibit human lymphocyte mitogenesis.
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PMID:Analysis of the in vitro effect of exogenous nitric oxide on human lymphocytes. 920 99

The BCR/ABL oncogene causes human chronic myelogenous leukemia (CML), a myeloproliferative disease characterized by massive expansion of hematopoietic progenitor cells and cells of the granulocyte lineage. When transfected into murine hematopoietic cell lines, BCR/ABL causes cytokine-independence and enhances viability. There is also growing evidence that p210(BCR/ABL) affects cytoskeletal structure. p210(BCR/ABL) binds to actin, and several cytoskeletal proteins are tyrosine phosphorylated by this oncoprotein. Also, at least one aspect of cytoskeletal function is abnormal, in that the affinity of beta1 integrins for fibronectin is altered in CML cells. However, isolated changes in beta1 integrin function would be unlikely to explain the clinical phenotype of CML. We used time-lapse video microscopy to study cell motility and cell morphology on extracellular cell matrix protein-coated surfaces of a series of cell lines before and after transformation by BCR/ABL. BCR/ABL was associated with a striking increase in spontaneous motility, membrane ruffling, formation of long actin extensions (filopodia) and accelerated the rate of protrusion and retraction of pseudopodia on fibronectin-coated surfaces. Also, while untransformed cells were sessile for long periods, BCR/ABL-transformed cells exhibited persistent motility, except for brief periods during cell division. Using cell lines transformed by a temperature-sensitive mutant of BCR/ABL, these kinetic abnormalities of cytoskeletal function were shown to require BCR/ABL tyrosine kinase activity. Similar abnormalities of cytoskeletal function on fibronectin-coated surfaces were observed when hematopoietic progenitor cells purified by CD34 selection from patients with CML were compared with CD34 positive cells from normal individuals. Interestingly, alpha-interferon treatment was found to slowly revert the abnormal motility phenotype of BCR/ABL-transformed cells towards normal. The increase in spontaneous motility and other defects of cytoskeletal function described here will be useful biological markers of the functional effects of BCR/ABL in hematopoietic cells.
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PMID:BCR/ABL induces multiple abnormalities of cytoskeletal function. 920 56

It is believed that long-term cultures of CML marrow cells favor the outgrowth of BCR/ABL negative hematopoietic progenitor cells (HPC) and that this phenomenon may be enhanced with negative hematopoietic regulators which can maintain primitive HPC in a quiescent state. Proliferation of CML marrow CD34+ cells in primary short-term cultures, maintained in the presence or absence of macrophage inhibitory protein-1 alpha (MIP-1 alpha), was tracked with the membrane dye PKH2. After 7 to 10 days it was possible to distinguish between cytokine responsive (CR) CD34+ cells (cells which had divided thus becoming PKH2dim) and cytokine nonresponsive (CNR) CD34+ cells (cells which had not divided and had therefore remained PKH2bright). CR and CNR CD34+ cells were isolated by flow cytometric cell sorting, seeded in secondary long-term cultures, and their progeny cells assayed weekly for their clonogenic progenitor cell content and expression of BCR/ABL by reverse transcriptase polymerase chain reaction (RT-PCR). Whereas CNR cells isolated from control primary cultures (control/CNR) sustained in vitro hematopoiesis, similar cells from cultures treated with MIP-1 alpha (MIP-1 alpha/CNR) supported a higher and, in some patients, a more extended production of clonogenic HPC, indicating that MIP-1 alpha was able to maintain primitive HPC in a quiescent state. Predominance of BCR/ABL negative progenitors in vitro was more evident in secondary cultures initiated with CNR cells than in those initiated with CR cells, especially those established with MIP-1 alpha/CNR cells. Of interest is the observed decline in the percentage of BCR/ABL+ progenitors in these cultures with time. Whereas up to 100% of progenitors were BCR/ABL+ on day 0, by day 14, only 46% of progenitors in MIP-1 alpha/CNR secondary cultures were BCR/ABL+ and by day 28 and beyond, the percentage of BCR/ABL+ progenitors dropped to below 20%. These results suggest that the quiescent nature of normal HPC present in CML marrow may favor their identification via cell tracking and, subsequently, their isolation from the more actively cycling leukemic cells. These studies also confirm the feasibility of employing negative hematopoietic regulators to augment the sequestration of normal HPC among the cytokine nonresponsive fraction of CD34+ cells, an approach that may be clinically feasible for autotransplantation.
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PMID:Preferential sequestration in vitro of BCR/ABL negative hematopoietic progenitor cells among cytokine nonresponsive CML marrow CD34+ cells. 920 15

It has been shown that normal early progenitor or stem cells persist in the blood and bone marrow of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML); it is also known that normal haemopoietic progenitors can be expanded ex vivo in the presence of various cytokine combinations. The selection of normal (Ph-negative) progenitor cells from CML patients would potentially be of considerable clinical value for ex vivo purging and autologous transplantation. To obtain these cells. CD34-positive (progenitor) cells from the peripheral blood (PB) of CML patients were pretreated with 5-fluorouracil (5FU) (5 microg/ml) to suppress Ph-positive cells and then grown in suspension culture for 7 d with a combination of cytokines. We compared two combinations of cytokines: interleukin-1alpha (IL1alpha) and interleukin-3 (IL3) with either Flt3-ligand (FLT3L) or stem cell factor (SCF). Using these two combinations, we obtained the same degree of day 14 CFU-GM expansion (3.1 +/- 0.5 and 3.4 +/- 0.7 fold expansion). FISH analysis showed that 5FU pretreatment significantly favoured a higher frequency of Ph-negative cells after expansion in liquid culture. Moreover, after 5FU pretreatment, the mean (+/-SEM) percentage of Ph negativity was significantly greater for IL1alpha-IL3-FLT3L compared to IL1alpha-IL3-SCF (19.1 +/- 2.5% v 14.8 +/- 2.3%, P=0.009, n = 7). The output long-term culture initiating cells (LTC-IC) which could only be detected after 5FU pretreatment and the combination, IL1alpha-IL3-FLT3L were all Ph negative by FISH analysis. Thus, a subset of Ph-negative cells was selected from CML PB by 5FU and expanded using the combination of cytokines IL1alpha-IL3-FLT3L and IL1alpha-IL3-SCF. Ex vivo expansion of putatively normal haemopoietic progenitor cells is feasible in CML.
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PMID:Ex vivo cytokine expansion of peripheral blood 5-fluorouracil-treated CD34-positive chronic myeloid leukaemia cells increases the selection of Ph-negative cells. 926 52

Two novel cell lines (JURL-MK1 and JURL-MK2) have been established from the peripheral blood of a patient in the blastic phase of chronic myelogenous leukemia. The cells grow in a single cell suspension with doubling times of 48 h (JURL-MK1) and 72 h (JURL-MK2). Cytogenetic analysis has shown that JURL-MK1 is hypodiploid whereas JURL-MK2 is near triploid and that both cell lines retain t(9;22). Moreover, JURL-MK1 and JURL-MK2 have a bcr/abl-fused gene with the same junction found in the patient's fresh cells, and both cell lines express the b3/a2 type of hybrid bcr/abl mRNA. The morphology and immunophenotype of these cell lines are reminiscent of megakaryoblasts. In both lines, a limited but consistent percentage of cells expresses gpIIbIIIa (CD41a), gpIIIa (CD61) and CD36, with no expression of gplb (CD42b), glycophorin A, hemoglobin and CD34. Both cell lines are clearly positive for CD33, CD43, CD45RO and CD63, while CD13, CD44, CD54, CD30 and CD40 are specific features of JURL-MK2. Among cytokine receptors, CD117/SCF-R is strongly displayed by a large fraction of JURL-MK1 cells but is hardly detectable on about 20% JURL-MK2 cells. Both cell lines are clearly positive for CD25/IL2R alpha, while a marked expression of CD116/GM-CSF-R and CDw123/IL3R alpha is restricted to JURL-MK2. Induction of cell differentiation in vitro has demonstrated that TPA is able to modulate the JURL-MK1 phenotype, causing an increased expression of platelet-associated antigens. The JURL-MK2 phenotype is easily modulated by both TPA and DMSO, which cause an increased expression of CD41a and CD117 accompanied by a decreased expression of CD30. Proliferation studies demonstrated that JURL-MK1 cell growth is enhanced by stem cell factor, while JURL-MK2 proliferation is unaffected by this cytokine. JURL-MK1 and JURL-MK2 are two novel cell lines with divergent biological features, representing a 'two-sided' model for investigating new aspects of megakaryocytopoiesis.
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PMID:JURL-MK1 (c-kit(high)/CD30-/CD40-) and JURL-MK2 (c-kit(low)/CD30+/CD40+) cell lines: 'two-sided' model for investigating leukemic megakaryocytopoiesis. 930 12

An important step in the oncogenic transformation of hemopoietic cells and the subsequent development of leukemia is the proliferation of tumor cells in the absence of exogenous growth factors. In most cases of chronic myelocytic leukemia and in some cases of acute myelocytic leukemia and acute lymphocytic leukemia, the bcr-abl oncogene is involved in this process. Although the BCR-Abl oncoprotein demonstrates enhanced tyrosine kinase activity in leukemic cells, the mechanism by which this leads to growth factor independence remains poorly defined. One proposed mechanism is the activation of cytokine signal transduction pathways, possibly by an autocrine loop involving IL-3 and/or granulocyte-macrophage CSF. Examination of several different cell lines expressing BCR-Abl demonstrates that some of these cells have constitutive activation of the JAK/STAT signaling pathway. We have found the constitutive activation of STAT5 in most, but not all, cell lines expressing BCR-Abl. This constitutive activation of STAT5 is variably associated with a corresponding activation of JAK kinases. Ab blocking studies show that the activation of STAT5 in these cell lines cannot be attributed to the activation of an IL-3/granulocyte-macrophage CSF-driven autocrine loop. Interestingly, samples of peripheral blood cells derived from patients with acute myelocytic leukemia and chronic myelocytic leukemia, which express BCR-Abl, demonstrate constitutive activation of STAT family members. These studies suggest that in a variety of leukemic states, BCR-Abl may use a bypass mechanism to activate cytokine signal transduction pathways.
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PMID:Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. 936 95

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.
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PMID:Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation. 938 68

Production of growth factors may provide a mechanism for disease evolution in some leukemias. Interleukin-1 is a plelotropic cytokine with the ability to synergize with other growth factors as well as to stimulate their production and release. Autocrine and/or paracrine secretion of interleukin-1 has been implicated in the pathogenesis of both chronic and acute myelogenous leukemia. Recently, a series of both specific and nonspecific IL-1 inhibitory molecules have been identified. These include IL-1 receptor antagonist, soluble IL-1 receptors, IL-1-converting enzyme inhibitor, IL-4, IL-10 and IL-1-antisense. Early experiments demonstrating the ability of some of these molecules to inhibit acute and chronic myelogenous leukemia growth suggest that clinical trials of these compounds may provide a novel management approach in these malignancies. Here we review the potential biologic and therapeutic role of IL-1 and its inhibitors in the myeloid leukemias.
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PMID:Interleukin-1 and its inhibitors: a biologic and therapeutic model for the role of growth regulatory factors in leukemias. 938 74

Today more than 80000 allogeneic bone marrow transplantations (BMT) have been performed worldwide. The major indications are hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and myelodysplastic syndromes. Unrelated donors are increasingly used and there are around 4 million volunteer donors available in different registers, the largest being the National Marrow Donor Program. Molecular typing has improved the typing technique which has resulted in a decreased risk of graft-versus-host disease (GVHD), lower transplant-related mortality (TRM) and improved leukemia-free survival (LFS). Using HLA-identical siblings, patients with AML in first complete remission (1 CR) and high-risk ALL in 1 CR are clear indications for BMT. However, if an HLA-identical sibling is not available, it is not known today if an unrelated bone marrow or autografting is the best option for all patients with acute leukemia in 1 CR. Because BMT is the only curable treatment for CML, a search for an unrelated donor should start as soon as it is evident that an HLA-identical sibling is not available. BMT within a year from diagnosis is of major importance for outcome. Allogeneic peripheral blood progenitor cells (PBPC) have been used as an alternative to bone marrow. Preliminary studies indicate a faster engraftment, but prospective randomized trials are necessary to establish the role of allogeneic PBPC. Umbilical cord blood has also been used as a source of allogeneic hematopoietic stem cells. Using cord blood from HLA-identical siblings, engraftment seems to be delayed, but the probability of GVHD is low. Preliminary data using unrelated cord blood cells are encouraging. GVHD has an important antileukemic effect. Recently, a graft-versus-myeloma and a graft-versus-breast-cancer effect has been demonstrated. In patients who relapse after BMT, donor lymphocytes can induce remission, especially in patients with CML. With molecular techniques it is possible to detect relapse at an early stage, so called minimal residual disease. Liposomal amphotericin B has few side-effects and decreased the death rate by invasive fungal infection in BMT recipients. Early diagnosis and treatment of cytomegalovirus (CMV) infection with new antiviral drugs have dramatically reduced the incidence and mortality in CMV disease. Cyclosporine combined with methotrexate is today the most widely used immunosuppressive regimen and has decreased GVHD and improved survival. However, several new immunosuppressive drugs need to be explored in clinical BMT. Immune modulation by for instance cytokines and cytokine inhibititors is a new exciting development.
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PMID:Allogeneic bone marrow transplantation for hematological malignancies--controversies and recent advances. 940 43


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