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)

We have previously shown that long-term cultures of adherent layers derived from patients with chronic myelogenous leukemia in blast crisis express high levels of interleukin (IL)-1 beta and that this cytokine may participate in disease progression. In this study, we analyzed cytokine expression in bone marrow adherent layers derived from patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). IL-6 messenger RNA (mRNA) was expressed in adherent layers established from four of nine MDS patients, and from 10 of 17 AML patients (including all four individuals in whom AML had evolved from an antecedent MDS state). Similarly, IL-1 beta mRNA was expressed in adherent layers derived from two of nine MDS patients and from three of 17 AML patients. Cultures from two of 10 AML patients who expressed IL-6 also expressed granulocyte (G) colony-stimulating factor (CSF) mRNA. In contrast, IL-1 beta, IL-6, and G-CSF mRNA were not discernible in adherent layers from any of 14 normal volunteers. Transforming growth factor-beta 1, macrophage (M) CSF, IL-7, and leukemia inhibitory factor mRNA as well as IL-6 protein were constitutively expressed in adherent layers derived from both MDS patients, AML patients, and normal bone marrows, whereas IL-1 alpha, tumor necrosis factor-alpha, and GM-CSF were not expressed in either the normal-, MDS- or AML-derived adherent layers. These results indicate that cultured stroma from a subset of MDS and AML patients produce IL-1 beta and/or IL-6. Although, exposure of adherent layers to exogenous IL-1 beta was able to induce IL-6 expression, in 9 of the 14 samples constitutively expressing cytokines, IL-6 transcript levels were elevated without a concomitant increase in IL-1 beta, suggesting that IL-6 transcription was independently dysregulated.
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PMID:Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia. 783 15

Interleukin-4 (IL-4) is a cytokine with pleiotropic activities. In normal bone marrow cultures grown in the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), IL-4 suppresses granulocyte-macrophage colony-forming unit (CFU-GM) proliferation but it enhances the colony-stimulatory effect of granulocyte colony-stimulating factor (G-CSF). We studied the effect of IL-4 on chronic myelogenous leukemia (CML) bone marrow or peripheral blood cells from 30 patients using the CFU-granulocyte-erythrocyte-monocyte-megakaryocyte colony culture assay. In several repetitive experiments, IL-4 inhibited CFU-GM colony replication by 24 to 65% in a dose-dependent fashion at concentrations ranging from 0.01 to 10 micrograms/ml when patients' cells were cultured in the presence of erythropoietin alone or with phytohemagglutinin-conditioned medium, GM-CSF, or IL-3. The addition of 100 U/ml of IL-1 beta to the CML cultures partially reversed the inhibitory effect of IL-4. Incubation of CML low-density peripheral blood cells with IL-4 resulted in down-regulation of IL-1 beta and IL-6 production in three of four samples, suggesting that the suppressive effect of IL-4 is mediated by inhibition of IL-1 and by other mechanisms including inhibition of IL-6 production. In contrast to the stimulatory effect exerted by IL-4 on G-CSF-dependent CFU-GM progenitor proliferation in normal marrow, the addition of IL-4 to CML cultures grown in the presence of G-CSF resulted in a divergent effect: suppression of CML CFU-GM in two, stimulation in three, and no significant effect in two CML patients' samples. It is therefore possible that IL-4 may have an in vivo antiproliferative effect in a subpopulation of CML patients.
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PMID:Suppression of chronic myelogenous leukemia colony growth by interleukin-4. 842 75

The novel hematopoietic growth factor FLT3 ligand (FL) is the cognate ligand for the FLT3, tyrosine kinase receptor (R), also referred to as FLK-2 and STK-1. The FLT3R belongs to a family of receptor tyrosine kinases involved in hematopoiesis that also includes KIT, the receptor for SCF (stem cell factor), and FMS. the receptor for M-CSF (macrophage colony- stimulating factor). Restricted FLT3R expression was seen on human and murine hematopoietic progenitor cells. In functional assays recombinant FL stimulated the proliferation and colony formation of human hematopoietic progenitor cells, i.e. CD34+ cord and peripheral blood, bone marrow and fetal liver cells. Synergy was reported for co-stimulation with G-CSF (granulocyte-CSF). GM-CSF (granulocyte-macrophage CSF), M-CSF, interleukin-3 (IL-3), PIXY-321 (an IL-3/GM-CSF fusion protein) and SCF. In the mouse, FL potently enhanced growth of various types of progenitor/precursor cells in synergy with G-CSF, GM-CSF, M-CSF, IL-3, IL-6, IL-7, IL-11, IL-12 and SCF. The well-documented involvement of this ligand-receptor pair in physiological hematopoiesis brought forth the question whether FLT3R and FL might also have a role in the pathobiology of leukemia. At the mRNA level FLT3R was expressed by most (80-100%) cases of AML (acute myeloid leukemia) throughout the different morphological subtypes (MO-M7), of ALL(acute lymphoblastic leukemia) of the immunological subtypes T-ALL and BCP-ALL (B cell precursor ALL including pre-pre B-ALL, cALL and pre B-ALL), of AMLL (acute mixed-lineage leukemia), and of CML (chronic myeloid leukemia) in lymphoid or mixed blast crisis. Analysis of cell surface expression of FLT3R by flow cytometry confirmed these observations for AML (66% positivity when the data from all studies are combined), BCP-ALL (64%) and CML lymphoid blast crisis (86%) whereas less than 30% of T-ALL were FLT3R+. The myeloid, monocytic and pre B cell type categories also contained the highest proportions of FLT3R+ leukemia cell lines . In contrast to the selective expression of the receptor, FL expression was detected in 90-100% of the various cell types of leukemia cell lines from all hematopoietic cell lineages. The potential of FL to induce proliferation of leukemia cells in vitro was also examined in primary and continuously cultured leukemia cells. The data on FL-stimulated leukemia cell growth underline the extensive heterogeneity of primary AML and ALL samples in terms of cytokine-inducible DNA synthesis that has been seen with other effective cytokines. While the majority of T-ALL (0-33% of the cases responded proliferatively; mean 11%) and BCP-ALL (0-30%; mean 20%) failed to proliferate in the presence of FL despite strong expression of surface FLT3R, FL caused a proliferative response in a significantly higher percentage of AML cases (22-90%; mean 53%). In the panel of leukemia cell lines examined only myeloid and monocytic growth factor- dependent cell lines increased their proliferation upon incubation with FL, whereas all growth factor-independent cell lines were refractory to stimulation. Combinations of FL with G-CSF, GM-CSF, M-CSF, IL-3, PIXY- 321 or SCF and FL with IL-3 or IL-7 had synergistic or additive mitogenic effects on primary AML and ALL cells, respectively. The potent stimulation of the myelomonocytic cell lines was further augmented by addition of bFGF (basic fibroblast growth factor), GM-CSF, IL-3 or SCF. The inhibitory effects of TGF-beta 1 (transforming growth factor-beta 1) on FL- supported proliferation were abrogated by bFGF. Taken together, these results demonstrate the expression of functional FLT3R capable of mediating FL- dependent mitogenic signaling in a subset of AML and ALL cases further underline the heterogeneity of AML and ALL samples in their proliferative response to cytokine.
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PMID:Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. 861 33

The primary thrombocytosis (thrombocythemia) associated with myeloproliferative disorders is believed to be due to autonomous platelet production. Secondary or reactive thrombocytosis can be observed in a number of clinical circumstances, and may be related to persistent overproduction of some thrombocytopoietic factors acting on megakaryocytes. Several cytokines, including IL-6, IL-1 and IL-4 have been shown to act alone or in concert, to affect various cellular stages of megakaryocytopoiesis in humans. The aim of this study is to assess the serum concentrations of these cytokines in myeloproliferative disorders (MPD) with thrombocythemia and in rheumatoid arthritis (RA) with marked reactive thrombocytosis. Twenty-two patients (14 men, 8 women) with MPD and thrombocythemia (platelet counts > 500 x 10(9)/1; range 507-996 x 10(9)/1), 33 RA patients (28 women, 5 men) with marked thrombocytosis (platelet counts > 500 x 10(9)/1; range 500-745 x 10(9)/ 1), 27 RA patients (24 women, 3 men) with normal platelet counts (range 168-399 x 10(9)/1) and 15 healthy volunteers (8 women, 7 men) with normal platelet counts (range 161-385 x 10(9)/1) enrolled in the study. Serum IL-1 alpha, IL-1 beta, IL-4 and IL-6 concentrations were measured in these four groups. Of the 22 patients with MPD, 10 had chronic myelogenous leukemia, 5 had polycythemia vera, 6 had essential thrombocytosis and 1 had osteomyelofibrosis. Serum interleukin concentrations in patients with MPD and thrombocythemia were either suppressed or similar to those of normal subjects, whereas IL-6, IL-1 beta and IL-4 levels were increased in RA patients with reactive thrombocytosis. We conclude that thrombocythemia associated with MPD is an autonomous phenomenon, and is not regulated by cytokines which affect megakaryocytopoiesis.
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PMID:Megakaryocyte-related interleukins in reactive thrombocytosis versus autonomous thrombocythemia. 863 38

We have established a human stromal cell line derived from the bone marrow of a patient with chronic myelogenous leukemia in blast crisis. This cell line, designated FS-1, exhibits a fibroblastoid morphology and does not express any hematopoietic cell marker tested. FS-1 is negative for alpha-naphthyl acetate esterase, acetylated LDL, von Willebrand factor, and shows no phagocytosis. This cell line is positive for acid phosphatase, alkaline phosphatase, collagen types I, III, IV, and fibronectin. cDNA from FS-1 cells was subjected to amplification by the polymerase chain reaction to assess the constitutive expression of several cytokine genes. Transcripts for interleukin (IL)-6, IL-7, macrophage colony-stimulating factor (M-CSF), and stem cell factor (SCF) were detected in FS-1 cells. IL-6 and SCF also were detected in the culture supernatants of FS-1 at a concentration of 95 pg/ml and 21.2 pg/ml, respectively. These data show that FS-1, established from a human bone marrow, is a stromal cell line which was not generated using transfection with SV40 T antigen. FS-1 cells may be useful in supporting human hematopoietic cells for experimental manipulation.
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PMID:Establishment and characterization of a novel human bone marrow stromal cell line, FS-1. 872 43

Liver infiltrating lymphocytes (LIL) were isolated from HCV-positive (+) and HCV-negative (-) end-stage livers. Phenotypic analysis and functional studies using proliferative and lymphocytotoxic assays were performed with the isolated LIL. Two CD3+ lymphocyte populations were found in LIL using FITC anti-CD3 monoclonal antibodies (mAb). One was a bright fluorescence intensity population (as in PBL), and the other dim. We calculated the number of FITC-anti-CD3 mAbs bound per lymphocyte on PBL and LIL and found 80,040 +/- 4628 and 39,615 +/- 3932, respectively. Therefore, HCV+ and HCV- patient PBL contained approximately twice the number of CD3 molecules per cell than patient CD3+ LIL. LIL also contained approximately a threefold higher concentration of TCR alpha beta +, CD4-CD8-, and CD56,16 (NK) cells than the patient PBL. Thus, a major subset of LIL is phenotypically similar to mouse NK1.1+ "intermediate" T cells. LIL freshly isolated from HCV+ livers exhibited weak CTL activity against EBV- or Con A-transformed lymphoblast targets infected with vaccinia-HCV recombinant virus (rHCV) or primary hepatocyte cultured cells. However, after in vitro coculture of LIL with rHCV, these cells developed a strong cytotoxicity for the above targets. In contrast, LIL from HCV- livers were not cytotoxic against the same targets. Histochemical studies (in situ) demonstrated that these hepatocytes express CD95, and stains demonstrated apoptosis. The HCV+ hepatocytes also express class I MHC molecules and ICAM-1. The addition of mAb specific for these adhesion molecules inhibited CML activity. Short-term cultured hepatocytes (targets) from HCV+ and HCV- patients produced low levels of cytokines IL-1 beta, IL-2, IL-6, TNF alpha, and IFN-gamma but a high level of IL-8. It is speculated that LIL expressing reduced numbers of CD3 molecules may even function as immune regulators as proposed for intermediate T cells in mice.
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PMID:The immune reactivity role of HCV-induced liver infiltrating lymphocytes in hepatocellular damage. 908 90

Serum soluble interleukin-6 receptor (sIL-6R) concentrations were measured in 50 patients with plasma cell dyscrasias using a commercially available immunoenzymatic assay kit. There were 40 patients with multiple myeloma (MM), 5 patients with monoclonal gammopathy of undetermined significance (MGUS), 3 patients with solitary plasmacytoma (SPC), 1 patient with chronic myelogenous leukaemia and multiple myeloma (CML/MM), and 1 patient with plasma cell leukaemia (PCL). We found that serum sIL-6R concentrations were higher in MM patients (62.53 +/- 38.85 ng/ml) than in 20 normal volunteers studied (36.75 +/- 13.79 ng/ml) (p < 0.01). The cut-off value of 65 ng/ml seen in 2 of our controls was arbitrarily taken as the upper limit of the control range for serum sIL-6R; according to this criterion, 14 patients with MM (35%), 1 patient with SPC, the unique patient with CML + MM, and the unique patient with PCL had elevated concentrations of the receptor. Patients with MGUS had normal sIL-6R values. In MM patients, serum sIL-6R levels correlated with the clinical phase of the disease: they were elevated in patients with early or late active disease and ranged within normal limits in patients with plateau-phase disease (p < 0.001). Thirteen of 27 patients with active MM had elevated serum sIL-6R values, i.e. 48.1%, but only 1 out of 13 patients with disease in the plateau phase, i.e. 7.7% (p < 0.05). Furthermore, in the entire group of MM patients, serum sIL-6R levels correlated with the concentrations of serum beta 2-microglobulin, (p < 0.02), CRP (p < 0.01), ferritin (p < 0.01) and LDH (p < 0.01), while they did not correlate with disease stage, haemoglobin levels, proportion of marrow myeloma cells, the values of serum IL-6, the levels of serum albumin, or the grade of bone lesions. We conclude that elevated serum sIL-6R levels should be related to the growth of myeloma cells and suggest that serum sIL-6R concentrations may be used as an indicator of disease activity.
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PMID:Serum levels of soluble IL-6 receptor in multiple myeloma as indicator of disease activity. 915 60

We have previously reported that primitive normal hematopoietic cells detectable as long-term culture-initiating cells (Ph-LTC-IC) are present at high levels in the blood of some patients with chronic myeloid leukemia (CML). We now show that this population can be expanded several-fold when highly purified CD34+CD38- cells isolated from the blood of such patients are cultured for 10 days in a serum-free medium containing 100 ng/mL of Flt3-ligand and Steel factor and 20 ng/mL of interleukin-3 (IL-3) and IL-6, and granulocyte colony-stimulating factor. In similar cultures initiated with CD34+CD38- cells from CML blood samples in which all of the LTC-IC were leukemic (Ph+), Ph+ LTC-IC activity was rapidly lost both in the presence and absence of admixed CD34+CD38- cells isolated from normal marrow. Conversely, the ability of normal LTC-IC to expand their numbers was shown to be independent of the presence of Ph+LTC-IC and later types of Ph+colony-forming cell (CFC) progenitors. In contrast to the LTC-IC, CFC were consistently amplified in cultures initiated with CML-derived CD34+CD38- cells and the additional CFC present after 10 days were, like the starting population of CFC, almost exclusively Ph+ regardless of the genotype(s) of the LTC-IC in the original CML samples. Amplification of the Ph+CFC population in these cultures showed the same factor dependence as previously demonstrated for the in vitro expansion of CFC from normal marrow CD34+CD38- cells. Ph+LTC-IC disappeared regardless of the cytokines present. Taken together these findings support a model of CML in which the leukemic stem cells are characterized by a decreased probability of self-renewal and an increased probability of differentiation. In addition, they suggest new opportunities for improving the treatment of CML using strategies that require autologous stem cell rescue.
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PMID:Selective expansion of primitive normal hematopoietic cells in cytokine-supplemented cultures of purified cells from patients with chronic myeloid leukemia. 920 39

FACS-selected CD34+ HLA-DR- cells (DR- cells) may provide a source of benign stem cells suitable for autografting in chronic myelogenous leukemia (CML) and other hematological malignancies. However, DR- cell selection depletes the majority of committed hematopoietic progenitors, which may be important for early engraftment. Furthermore, only a small number of DR- cells may be selectable in certain patients. These impediments to the use of DR- cells for autografting may be overcome through the development of ex vivo culture systems that support expansion and initial differentiation of primitive progenitors. Because 2-week culture of DR- cells in a stroma "noncontact" system supplemented with interleukin-3 (IL-3) and macrophage inflammatory protein 1-alpha (MIP-1alpha) expands both long-term culture-initiating cells (LTC-ICs) and colony-forming cells (CFCs), we adapted this system to a clinically applicable method for expanding LTC-ICs and CFCs ex vivo. In initial small-scale studies, DR cells were grown in stroma conditioned medium (SCM) supplemented with IL-3 with or without additional growth-promoting cytokines and the chemokines PF-4 and BB10010, all approved for clinical use. An IL-3 dose-dependent expansion of committed progenitors and LTC-ICs was observed when DR- cells were cultured in tissue culture plates in SCM+IL-3 for 2 weeks. Similar CFC expansion along with increased (5-fold) LTC-IC expansion was observed following addition of PF-4 to SCM+IL-3 cultures. The addition of stem cell factor (SCF), but not of IL-6, IL-11, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, IL-1, and IL-7, increased CFC and LTC-IC expansion beyond the levels observed with SCM+IL-3 alone. We next evaluated the suitability of this culture system for scale-up. Culture of 2-6 x 10(5) DR- cells in gas-permeable bags with SCM+IL-3 resulted in similar CFC and LTC-IC expansion as seen in small-scale cultures. In addition, we observed that progenitors capable of differentiating to natural killer (NK)-cells were maintained under these conditions. Finally, we found that BCR/ABL mRNA-negative CFCs and LTC-ICs present in DR- cells selected from steady-state CML marrow could be expanded in large-scale SCM+IL-3 cultures. We conclude that culture of DR- cells for 2 weeks in SCM+IL-3 culture, with or without PF-4 or SCF, results in significant CFC and LTC-IC expansion and lymphoid NK progenitor maintenance. This culture system is readily adaptable to the expansion of primitive progenitors for autotransplantation.
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PMID:A clinically suitable ex vivo expansion culture system for LTC-IC and CFC using stroma-conditioned medium. 925 12

Plasma concentrations of interleukines 1, 3, 6, 8 and platelet derived growth factor (PDGF) were estimated in 45 patients with leukaemias. Among patients were 12 with acute myeloblastic leukaemia-AML (type M1 according to FAB classification), 9 with chronic granulocytic leukaemia-CGL, 10 with blastic crisis of CGL (CGL-BC) and 14 with chronic lymphocytic leukaemia-CLL (in 1 and 2 stage according to Rai classification). Additionally the concentration of IL-3 was measured in 10 patients with exacerbation of CLL. Control group consisted of 12 health volunteers. The concentrations of interleukines and PDGF were determined by means of radioimmunoassay or immunoradiometric assay. In the patients with AML, CGL-BC and CLL significant increase of concentrations of IL-1B, IL-6 were found. The patients suffers from CGL and CGL-BC had increase concentrations of IL-3, but patients with CLL-interleukin 8. The concentrations of PDGF were significantly decreased in the patients with AML, CGL-BC, and CGL. The differences of concentrations of studied interleukines can confirm their great significance in proliferation of leukaemic cells. The decrease of concentrations of PDGF in myelocytic leukaemias may reflect thrombopoietic disturbances in these illnesses.
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PMID:[Examination of interleukin levels and growth factor from blood platelets in leukemia]. 928 10


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