{"title":"The cellular and molecular environment in leukemia.","authors":"L Sachs","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Identification of normal viability-, growth-, and differentiation-inducing cytokines, the cells that produce them, and how cytokines interact in normal development, has made it possible to identify the cellular and molecular basis of normal development and changes in the developmental program that result in leukemia. When normal cells have been changed into leukemic cells, the malignant phenotype can again be suppressed in various ways. Results on the molecular control of growth, differentiation, and apoptosis in normal myeloid hematopoietic cells, changes in the normal developmental program in myeloid leukemia, and the suppression of malignancy in myeloid leukemia, have shown that (A) malignancy can be suppressed either with or without genetic changes in the tumor cells, (B) suppression of malignancy by inducing differentiation does not have to restore all the normal controls, and (C) genetic abnormalities which give rise to malignancy can be bypassed and their effects nullified by inducing differentiation and apoptosis which stop cells from multiplying.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 3","pages":"709-26; discussion 727-30"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19013310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The history of leukemia: a personal perspective.","authors":"G Piller","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A brief review of the history of human leukemia, first identified as a new disease in 1845, is given as a personal perspective related to the re-examination of dogmas surrounding the disease. The paper addresses the question of what kind of disease leukemia is, and how far the adherence to dogma has shaped the firm belief that leukemia is a malignancy.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 3","pages":"521-9; discussion 530-5"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19014745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Z Y Wang, Z Chen, W Huang, X S Li, J X Lu, L A Huang, F Q Zhang, L J Gu, R R Ouyang, S J Chen
{"title":"Problems existing in differentiation therapy of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA).","authors":"Z Y Wang, Z Chen, W Huang, X S Li, J X Lu, L A Huang, F Q Zhang, L J Gu, R R Ouyang, S J Chen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A large number of acute promyelocytic leukemia (APL) patients, treated with all-trans retinoic acid (ATRA) and chemotherapy, were studied. The results of the studies are as follows: (1) Among 65 patients investigated for the postremissional therapy, the 5-year survival probabilities were 0.20 +/- 0.13 (mean +/- SE) in the group treated with ATRA alone, 0.47 + 0.10 (mean +/- SE) in the group using chemotherapy alone and 0.42 +/- 0.09 (mean +/- SE) in the group treated with chemotherapy and ATRA. (2) The main severe adverse effects in the ATRA treatment include retinoic acid syndrome, renal failure, and thrombosis. These sequelae were observed more frequently in cases with persistent, marked elevation of white blood cell count without significant maturation of leukemic promyelocytes. (3) APL is not a homogeneous disease in that among 50 patients studied at the molecular level, although a PML-RARA fusion gene was detected in 45 cases, one had a variant translocation t(11;17) bearing fusion gene PLZF-RARA, one presented no obvious structural alteration of the PML gene while the RARA gene was rearranged, and three patients had no rearrangement of either PML or RARA genes. (4) Using RT/PCR to detect minimal residual disease, we found positive rates of 22%, 18.4%, and 11.5%, respectively, 12, 24, and 36 months after CR. This observation justifies the use of chemotherapy for at least 3 years after CR induced by ATRA. (5) It seems likely that the fusion gene PML-RARA plays an important role in APL leukemogenesis and in its response to the ATRA treatment.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 3","pages":"633-41; discussion 642-7"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19014753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Involvement of multiple kinases in neutrophil activation.","authors":"D J Lu, W Furuya, S Grinstein","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Production of reactive oxygen metabolites by the NADPH oxidase is an essential mechanism underlying the microbicidal role of phagocytes. Receptor-mediated activation of the oxidase was originally thought to be mediated by calcium and/or by protein kinase C (PKC). However, recent evidence suggests that additional signalling pathways exist. In this article the possible role of tyrosine phosphorylation is discussed. In addition, results obtained using an in vitro kinase renaturation assay are described. The latter assay revealed the existence of at least four serine/threonine kinases that are activated in cells stimulated with chemoattractants. One of these, of molecular weight 41,000 was identified as a member of the ERK or MAP-kinase family. The existence of multiple, possibly redundant or synergistic signaling pathways is considered.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 2","pages":"343-9; discussion 349-51"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19300499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibition of sickling after reduction of intracellular hemoglobin concentration with an osmotic pulse: characterization of the density and hemoglobin concentration distributions.","authors":"R S Franco, R Barker-Gear, R Green","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Hemoglobin S polymerization is markedly dependent on intracellular hemoglobin concentration. In the studies presented here, sickle RBC were subjected to a transient osmotic stress, which induced a short period of increased membrane permeability and allowed partial efflux of Hb S. Morphological sickling of the resulting hypochromic RBC was inhibited. The response of RBC to this osmotic pulse is influenced by the presence of a polyanion, which in these experiments was either inositol hexaphosphate (IHP, 27 mM or 46 mM) or pyrophosphate (69 mM or 95 mM). The decrease in MCHC, measured manually, ranged from 3.1 +/- 1.7 (1 SD) to 6.3 +/- 2.8 g/dl, depending on the conditions used during modification. Parallel electronic analysis of RBC indices demonstrated a comparable decrease in MCHC which was due to both an increased MCV and a decreased MCH. Since the modified cell population is quite heterogeneous, cells were analyzed using discontinuous stractan gradients and/or a laser-based instrument which measures the hemoglobin concentration (HC) of individual cells. For most treatment conditions, the modified cells have a bimodal HC distribution with one peak centered at about 20 g/dL and the other peak corresponding to the unmodified cells. With the higher concentration of IHP, however, many cells had an intermediate HC. For modified RBC with a bimodal HC distribution (27 mM IHP, 69 mM PP, 95 mM PP), inhibition of morphological sickling was proportional to the change in HC and there were no subpopulations with an increased tendency to undergo sickling. However, the intermediate density cells present when RBCs were treated with the higher concentration of IHP underwent sickling at a higher oxygen partial pressure than control cells.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 2","pages":"475-88; discussion 489-91"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19299106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure and function of human and mouse Fc gamma RII.","authors":"R J Looney","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Receptors for the Fc portion of IgG play an important role in translating the hormonal immune response into activation of various effector cells. Some of the many processes mediated via Fc gamma Rs include endocytosis, phagocytosis, ADCC, superoxide generation, and secretion of lysosomal enzymes and cytokines. There are three different classes of Fc gamma R in humans and mice. These receptors are found on a wide variety of cells including platelets, neutrophils, eosinophils, monocytes, macrophages, large granular lymphocytes, and B lymphocytes. The cDNAs for the human Fc gamma Rs have been cloned and their structures elucidated by sequencing. Recent studies have demonstrated that the cytoplasmic domains of these receptors are crucial for signal transduction. Moreover, there is evidence that different processes triggered by the same receptor seem to require different regions of the cytoplasmic domain. This review will discuss these recent studies correlating Fc gamma R structure and function.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 2","pages":"353-9"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19300500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dynamic aspects of cytoskeletal protein distribution in T lymphocytes: involvement of calcium in spectrin reorganization.","authors":"C C Gregorio, J D Black, E A Repasky","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Our studies on the lymphocyte cytoskeleton have revealed a significant heterogeneity in the subcellular distribution of lymphocyte spectrin in vivo. Two model systems have been characterized in which this protein exhibits dynamic properties in response to activation signals. In this study, we have investigated the role of calcium in the activation-induced reorganization of spectrin in one of these systems, the DO-11.10 T cell hybridoma. DO-11.10 cells, as well as several other in vitro T cell models, can homogeneously and constitutively express a distinct cytoplasmic aggregate of spectrin that is rapidly fragmented upon activation. The reversible dissipation of the aggregate of spectrin is accompanied by an increase in the levels of spectrin diffusely distributed throughout the cytoplasm and at the plasma membrane. Pretreatment of cells with calcium-free medium, or with medium containing ethyleneglycol-bis-(beta-aminoethyl ether)N,N'-tetraacetic acid (EGTA) or verapamil, significantly blocked the reorganization of spectrin induced by Concanavalin A or the calcium ionophore A23187, and also prevented the release of IL-2 from these cells. Further, immunofluorescent and ultrastructural analyses revealed abnormalities in the organization of spectrin induced by these treatments. These findings are discussed in light of our other studies, indicating a role for spectrin in early events associated with activation of T lymphocytes in vivo and in vitro.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 2","pages":"361-71; discussion 371-3"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19300501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neutrophil adhesion to endothelial cells.","authors":"O Abbassi, T K Kishimoto, L V McIntire, C W Smith","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The emigration of neutrophils at sites of inflammation apparently requires intercellular adhesion. Initially, leukocyte adherence is observed in postcapillary venules where neutrophils roll along the luminal surface of the endothelial cells before stopping, changing shape, and migrating into the perivascular tissue. Recent evidence indicates that the adhesion molecules supporting the rolling phenomenon are distinct from those required for stopping and transmigration. The contribution of E-selectin (ELAM-1) to neutrophil adhesion and rolling was investigated using anti-E-selectin monoclonal antibody in an in vitro adhesion assay of isolated human neutrophils to murine L-cell monolayers stably transfected with human E-selectin cDNA. Isolated human neutrophils adhered to E-selectin expressing L-cell monolayers under physiological wall shear stress of 1.85 dynes/cm2 but not to untransfected L-cells or ICAM-1 expressing L-cells. 47.8 +/- 6.0% of these adherent cells were rolling at an average rolling velocity of 10.6 +/- 1.7 microns/second. This adhesion and rolling was almost completely blocked by anti-E-selectin monoclonal antibody. Monoclonal antibody to L-selectin also reduced adhesion to E-selectin expressing cells by 70%. Chemotactic stimulation of neutrophils reduced both the number of adherent and rolling cells and the average velocity of the rolling cells without influencing the percentage of attached cells that were rolling. Pretreatment with anti-CD18 monoclonal antibody did not reduce the adhesion of the activated neutrophils but reversed the reduction in velocity caused by activation of these cells. The inhibitory potential of the anti-E-selectin monoclonal antibody was much less pronounced in adhesion of isolated neutrophils to human umbilical vein endothelial cell monolayers under conditions of flow and was limited to one third of the total adhesion. The proportion of the adherent neutrophils which transmigrated to the subluminal space of the endothelial cell monolayers was independent of pretreatment with anti-E-selectin monoclonal antibody.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 2","pages":"245-59; discussion 259-60"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18518692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ion channels and receptor-mediated Ca2+ influx in neutrophil granulocytes.","authors":"K H Krause, N Demaurex, M Jaconi, D P Lew","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Although generally classified as non-excitable cells, human neutrophils possess a variety of ion channels that play a crucial role in the regulation of cellular activity. The mechanism of receptor-mediated Ca2+ influx in neutrophils is complex. Receptor agonists empty intracellular Ca2+ stores via generation of Ins(1,4,5)P3. The emptying of intracellular Ca2+ stores leads by an hitherto not understood mechanism to the activation of Ca2+ influx across the plasma membrane. Neutrophils possess at least 2 types of K+ channels. Voltage-activated K+ channels, important for the maintenance of the resting potential, and Ca2+ activated K+ channels, important for the repolarization after cellular activation. Neutrophils also possess voltage- and pH activated H+ channels that serve to extrude protons, generated by the neutrophil respiratory burst. Neutrophils depolarize in response to activation by agonists. The mechanism of neutrophil depolarization involves electron transport by the respiratory burst oxidase. Neutrophil depolarization serves as a negative feed-back mechanism, it also activates the H+ channels and thereby stimulates extrusion of protons.</p>","PeriodicalId":75604,"journal":{"name":"Blood cells","volume":"19 1","pages":"165-73; discussion 173-5"},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18694266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}