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)

Current evidence suggests that the expression of the tyrosine kinase p210bcr/abl in chronic myelogenous leukemia (CML) may directly induce the initial phase of granulocytic hyperplasia. However, the dysregulation of additional genes appears to be required for transition to the acute leukemic phase, as inferred by the appearance of recurrent secondary cytogenetic abnormalities in the majority of patients. To determine whether the expression of p210bcr/abl alone is responsible for this genetic instability, we introduced and expressed the bcr/abl gene from a retroviral vector in a clone of the interleukin-3 (IL-3) dependent myeloblastic 32D C13(G) cell line. Clonal and polyclonal cells transformed to IL-3 independent growth were observed for a period extending up to 6 months for changes in the expression of p210bcr/abl, cell proliferation, inhibition by prostaglandin E1 (PGE1), forskolin, and cyclic adenosine monophosphate (cAMP) analogues, regulation of the cell cycle, and karyotype. Whereas the properties of control vector infected 32D C13(G)' cells remained stable over time, cells expressing p210bcr/abl were phenotypically unstable. In cells expressing p210bcr/abl, we observed selective modulation of p210bcr/abl mRNA and protein expression, evolution from partial to full abrogation of IL-3 dependence, reduced serum requirements, increased cell proliferation, decreased inhibition by PGE1 and cAMP analogues, and the appearance of new structural and numerical chromosomal abnormalities with successive cell passages. These results indicate that expression of p210bcr/abl can directly predispose 32D C13(G)' cells to genetic instability, promotes the emergence of clones with an increased proliferative advantage, and may represent an in vitro model suitable for the study of mechanisms underlying progression to the acute leukemic phase in CML.
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PMID:Clonal evolution in a myeloid cell line transformed to interleukin-3 independent growth by retroviral transduction and expression of p210bcr/abl. 132 83

Recent data suggest that prostaglandins (PGs) are involved in the regulation of basophil activation. The aim of this study was to characterize the basophil PG-binding sites by means of radioreceptor assays using 3H-labeled PGs. Scatchard analysis for pure (greater than 95%) chronic myeloid leukemia (CML) basophils revealed two classes of PGE1-binding sites differing in their affinity for the natural ligand (Bmax1 = 217 +/- 65 fmol/10(8) cells; Kd1 = 0.5 +/- 0.2 nM; Bmax2 = 2462 +/- 381 fmol/10(8) cells; Kd2 = 47 +/- 20 nM; IC50 = PGE1 less than PGI2 less than PGD2 less than PGE2 less than PGF2 alpha) as well as two classes of PGI2 (iloprost)-binding sites (Bmax1 = 324 +/- 145 fmol/10(8) cells; Kd1 = 0.5 +/- 0.3 nM; Bmax2 = 2541 +/- 381; Kd2 = 27 +/- 6 nM; IC50 = PGI2 less than PGE1 less than PGD2 less than PGE2 less than PGF2 alpha. In addition, CML basophils exhibited a single class of PGD2-binding sites (Bmax = 378 +/- 98 fmol/10(8) cells; Kd = 13 +/- 4 nM; IC50: PGD2 less than PGI2 less than PGE1 less than PGE2 less than PGF2 alpha). In contrast, we were unable to detect specific saturable PGE2-binding sites. Primary and immortalized (KU812) CML basophils revealed an identical pattern of PG receptor expression. Basophils (KU812) expressed significantly (p less than 0.001) lower number of PGE1 (PGI2)-binding sites (Bmax1: 9% (20%) of control; Bmax2: 36% (50%) of control) when cultured with recombinant interleukin 3 (rhIL-3), a basophil-activating cytokine, whereas rhIL-2 had no effect on PG receptor expression. Functional significance of binding of PGs to basophils was provided by the demonstration of a dose-dependent increase in cellular cAMP upon agonist activation, with PGE1 (ED50 = 1.7 +/- 1.1 nM) and PGI2 (ED50 = 2.8 +/- 2.3 nM) being the most potent compounds. These findings suggest that human basophils express specific receptors for PGE1, PGI2 as well as for PGD2.
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PMID:Characterization of prostaglandin (PG)-binding sites expressed on human basophils. Evidence for a prostaglandin E1, I2, and a D2 receptor. 137 73

The iron-binding proteins lactoferrin (LF) and H-ferritin have been implicated in the negative regulation of myelopoiesis in vitro and in vivo. The present studies evaluated the functional activity of affinity-purified LF from polymorphonuclear neutrophils (PMN) of patients with chronic myelogenous leukemia (CML) and LF/H-ferritin-cell interactions in a nonleukemic patient with LF deficiency with normal levels of circulating blood leukocytes. Affinity-purified CML-PMN-LF was found to be qualitatively deficient as a suppressor of the release of colony-stimulating factors from mononuclear blood cells, adding to previous information from our group documenting defective LF-cell interactions in CML. LF was detected by immunoradiometric assay in PMN of the patient with LF deficiency, but at a much lower level than normal. This LF was found, however, to be active as a suppressor molecular against the patient's cells and normal donor cells. Patient cells were as responsive as normal cells to effects of purified milk LF. Decreased LF levels in this patient were associated with increased levels of monocyte H-ferritin inhibitory activity, consistent with the known suppressive effects in vitro of LF on H-ferritin release from monocytes. Patient marrow hematopoietic progenitor cells were as responsive as progenitors from normal donors to suppression by purified H-ferritin and prostaglandin E1. These results are consistent with a role of LF and H-ferritin in the control of myelopoiesis in this patient.
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PMID:Qualitative functional deficiency of affinity-purified lactoferrin from neutrophils of patients with chronic myelogenous leukemia, and lactoferrin/H-ferritin-cell interactions in a patient with lactoferrin-deficiency with normal numbers of circulating leukocytes. 204 67

The effects of a synthetic prostaglandin E1 (PGE1) analog on colony-forming activity in agar cultures of peripheral blood and bone marrow was studied in 28 patients with chronic myeloid leukemia and 9 hematologically healthy subjects. Addition of PGE1 to normal bone marrow culture was followed by a significant drop in the number of colonies per dish in 8 out of the 9 subjects. In leukemic patients, the effect was bizarre. It proved to be in correlation with survival thus suggesting that the effect of PGE1 on colony-forming activity of granulocyte-macrophage precursors be used in predicting survival in patients with chronic myeloid leukemia.
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PMID:[A method for predicting the course of chronic myeloleukemia]. 225 15

Using the megakaryocytic leukemia cell lines, K-562 and CMK established from a Down's patient with acute megakaryoblastic leukemia, we studied the changes of antigen expression, cytosolic Ca2+ mobilization, thromboxane (TX) A2 formation and gene expression during megakaryocyte differentiation. We found that thrombospondin synthesis and platelet factor (PF)-4 gene expression were specific for mature megakaryoblasts, whereas collagen unresponsiveness and prostaglandin E1-induced Ca2+ mobilization were noted in immature megakaryoblasts alone. This experiment shows that functional and genetic analysis are useful for characterizing the leukemic megakaryoblastic cells. We analyzed the clinical, hematologic and genetic features of 4 patients with M7, and acute megakaryoblastic transformation of CML, MDS and essential thrombocythemia. In two patients, prednisolone and 6-MP were effective in cytoreduction. In 3 patients with increased platelet counts, normal CFU-Meg formation, the megakaryoblasts with platelet production, or the coexistence of immature megakaryoblasts with mature megakaryocytes were observed, thus indicating that some megakaryoblastic leukemia cells still have the capacity of differentiation. One patient had megakaryoblastic cells with PF-4 gene expression. These clinical findings suggest that the megakaryoblastic leukemia could not be characterized as usual leukemia and a more sensitive marker is required to differentiate leukemic megakaryoblasts from normal megakaryoblasts.
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PMID:[Megakaryocytic leukemia cell lines and megakaryocytic leukemia]. 238 Oct 77

Prostaglandins of the E series (PGE) inhibit proliferation of normal bone marrow granulocyte/macrophage progenitors (CFU-GM). Circulating CFU-GM are known to differ from marrow CFU-GM in many characteristics, and in the present study, we compared the effect of PGE1 on circulating and bone marrow progenitors in normals and in patients with chronic myelogenous leukemia (CML). PGE1 caused a dose-dependent inhibition of normal marrow CFU-GM. Circulating CFU-GM were inhibited only at concentrations of 10(-5) mol/L or greater, and progenitor proliferation was, in fact, significantly stimulated at PGE1 concentrations between 10(-8) and 10(-6) mol/L. Bone marrow CFU-GM from patients with CML were inhibited in a manner similar to that of normal bone marrow. Circulating cells from patients with CML were, however, less sensitive to PGE1 inhibition than CML bone marrow cells and demonstrated a pattern intermediate between normal circulating and normal marrow progenitors. These studies suggest that peripheral blood and bone marrow contain different progenitor cell populations.
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PMID:Granulocyte/macrophage progenitor cells from peripheral blood and bone marrow differ in their response to prostaglandin E1. 349 44

The influence of prostaglandin E1 (PGE1) on colonies produced by different subtypes of committed granulomacrophagic precursors (CFU-GM) was studied. Even though they represent a more immature class of precursors than day 7 CFU-GM, day 14 CFU-GM have the same sensitivity to PGE1: their growth is significantly inhibited by low PGE1 concentrations (10(-10) M or higher). Macrophagic colony formation is most sensitive to PGE1. Pure granulocytic colonies are relatively resistant and significantly inhibited by high concentrations only. Mixed granulomacrophagic colonies display an intermediate degree of sensitivity. Both day 7 and day 14 CFU-GM from chronic myeloid leukemia and idiopathic myelofibrosis patients are significantly less sensitive than normal CFU-GM. This insensitivity is not dependent on a lack of production of macrophagic colonies, since these may even be present in a higher than normal frequency.
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PMID:Responsiveness to prostaglandin E1 of different subtypes of normal and pathological committed granulomonopoietic precursors. 640 61

The influence of E prostaglandins on the in vitro growth of chronic myeloid leukemia (CML)-committed granulopoietic precursors [colony-forming unit-culture (CFU-C)] has been investigated in a double-layer agar system in which CFU-C growth was stimulated by adherent monocytes. Addition of the prostaglandin synthesis inhibitor indomethacin to the feeder layer significantly increased the number of normal CFU-C, whereas CML CFU-C were unaffected. Exogenous prostaglandin E1 inhibited CML CFU-C growth at concentrations 1000-fold higher than those necessary to produce a similar effect on normal CFU-C. These data point to a lower than normal sensitivity of CML-committed granulopoietic precursors. It is suggested that derangement of the responsiveness of CML cells to prostaglandin regulation may play a role in the pathogenesis of uncontrolled leukemic proliferation.
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PMID:Insensitivity of chronic myeloid leukemia cells to inhibition of growth by prostaglandin E1. 693 Mar 23

The formation of myeloid colonies in soft-agar cultures of normal human marrow was markedly inhibited by prostaglandin E. Morphological characterization of colonies in the presence or absence of prostaglandin E1 showed that inhibition was restricted to monocytoid rather than neutrophil differentiation. Myeloid colony formation by granulocyte-macrophage-commited colony-forming cells from patients with chronic myeloid leukemia was not inhibited even by high concentrations of prostaglandin E and was independent of colony morphology. The altered sensitivity of leukemic colony-forming cells to prostaglandin E was observed at all stages of the disease and persisted following chemotherapy-induced reversion to a partial or complete Philadelphia chromosome-negative bone marrow status. This evidence suggests that altered myeloid stem cell sensitivity to a normal regulatory factor may play a role in the pathophysiology of chronic myeloid leukemia.
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PMID:Abnormal responsiveness of granulocyte-macrophage committed colony-forming cells from patients with chronic myeloid leukemia to inhibition by prostaglandin E1. 693 Mar 24

The behaviour of phagocytosis and that of PGE1 and PGE2 in the circulating granulocytes of normal and leukaemic subjects was investigated by the comparison of latex particles and the PAP (peroxidase-antiperoxidase) immuno-enzymatic method respectively. Generally speaking, it was found that chronic myeloid leukaemia and acute myeloblastic leukaemia were accompanied by a marked reduction in phagocyting capacity, whereas this is apparently normal in CLL and ALL. PCE values, on the other hand, were well down in lymphatic leukaemia, AML and AMML, but not in CML, where high PGE (especially PGE2) was noted both basally and after phagocytosis. That the PGE take part in phagocytosis is shown by their redistribution in phagocyting cells, with elective accumulation in the membrane and around the engulfed material.
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PMID:[Behavior of PGE1 and PGE2 in the granulocytes of normal and leukemic subjects during phagocytosis in vitro]. 695 84


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