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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-adherent cord blood and bone marrow mononuclear cells were analyzed by multiparameter flow cytometry before and at day 2, 4, 7, and 11 of culture in recombinant interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF, cord blood) or stem cell factor (SCF), IL3 and granulocyte-macrophage colony-stimulating factor (GM-CSF, BM) to assess the differentiation and maturational pathway of myeloid cells. Before cell culture cord blood contained progenitor cells (CD34+) in various differentiation stages (CD38(-)----CD38bright), mature lymphocytes, monocytes, and neutrophils, but no immature neutrophils and immature monocytes. During cell culture, all CD34+ cells acquired the CD38 antigen between day 2 and 5 of cell culture, the CD34 antigen was lost between day 5 and 11 of cell culture. Differentiation of cells into the myeloid cell lineage was characterized by the acquisition of both CD33 and CD71. The latter is indicative for the active proliferation of these cells. Maturation of the cells into the neutrophilic pathway was indicated by the acquisition of first the CD15 antigen followed by CD11b and CD16 respectively. Whereas maturation of the cells into the monocytic pathway was indicated by the acquisition of first CD11b followed by CD14 and a dim expression of both CD15 and CD16. In normal bone marrow, cells of various maturational stages are already present before cell culture. During cell culture differentiation of cells into the myeloid lineage and maturation of the cells along the monocyte and neutrophilic lineage followed identical pathways as was observed before cell culture. Differentiation and maturational pathways of cord blood and adult bone marrow were identical. The results confirm the surface-antigen-defined pathways of myeloid cell differentiation described previously for non-cultured normal bone marrow aspirates. The detailed assessment of cell maturation and differentiation of cultured cells by multidimensional flow cytometry permits the determination of the specific effects of various recombinant human growth factors on myeloid cells.
Leukemia 1992 Oct
PMID:Differentiation and maturation of growth factor expanded human hematopoietic progenitors assessed by multidimensional flow cytometry. 140 53

Studies on the structure of haemopoiesis in acute myeloblastic leukaemia (AML) has shown the presence of a small population of malignant cells with extensive proliferative and self-renewal properties which are features of stem cells. The requirements of these cells for proliferation have been studied both in clonogenic assays in semi-solid media and in liquid suspension culture. These have demonstrated that AML clonogenic cells from the majority of patients, can be stimulated to proliferate by colony-stimulating factors (GM-CSF, G-CSF and IL-3) as well as other cytokines including interleukin-1 and interleukin-6, all of which are known to stimulate normal haemopoietic progenitors. Unlike normal haemopoietic cells, leukaemic blasts from many patients with AML express transcripts for haemopoietic growth factors including GM-CSF, G-CSF and IL-1 but not IL-3, and secrete growth factor protein. When leukaemic cells are cultured at sufficiently high density to permit cell-cell interactions, autonomous growth of clonogenic cells can be seen. Autonomous growth is related to the autocrine secretion of haemopoietic growth factors including GM-CSF, G-CSF and IL-6. The degree of autonomous colony growth is variable but approximately 70% of AML samples exhibit either partial or totally autonomous growth; the remaining cells being absolutely dependent on exogenous CSF or fail to grow in the culture systems employed. Similar patterns of growth have been found in murine haemopoietic cells lines which have been transformed as the result of the retroviral insertion of genes for GM-CSF or IL-3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autocrine growth factors and leukaemic haemopoiesis. 142 83

Leukaemia inhibitory factor (LIF) is able to potentiate megakaryocyte colony formation in cultures of mouse bone marrow cells in the presence of multi-CSF (interleukin 3). Membrane receptors for LIF are present on mouse megakaryocytes and receptor numbers increase with increasing maturation of the cells. When injected into normal mice at doses of 0.2-2 micrograms two to three times daily, LIF induced a rise in platelet numbers, which reached up to twice normal values during the second week of injections. This rise was preceded by a rise first in megakaryocyte progenitor numbers, then in mature megakaryocytes in the bone marrow and spleen. Injections of LIF also marginally accelerated platelet regeneration in mice pre-injected with 5-fluorouracil or subjected to whole-body irradiation and transplantation of marrow cells. In view of similar responses to LIF in parallel studies in primates, clinical trial of LIF in patients with thrombocytopenia is warranted.
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PMID:Actions of leukaemia inhibitory factor on megakaryocyte and platelet formation. 142 12

Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.
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PMID:Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. 142 20

Loss of a whole chromosome 5 or deletion of 5q are recurring abnormalities in malignant myeloid neoplasms. Chromosomal loss or deletion are the hallmarks of tumour suppressor genes, suggesting that a gene(s) located on 5q may function as a leukaemia suppressor gene. To determine the location of genes on 5q that may be involved in myeloid leukaemogenesis, we examined the breakpoints of the del(5q) in a series of 117 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. A striking number of genes encoding haematopoietic growth factors have been mapped within or adjacent to the critical region. These include the genes encoding CSF-2, IL-3, IL-4, IL-5 and IL-9. By using fluorescence in situ hybridization, we have refined the localization of these genes to 5q31.1. To facilitate the identification of a tumour suppressor gene on 5q, we are currently preparing a physical map of 5q31. With FISH analysis of a series of cosmid and phage clones, we identified a number of clones within 5q31. By hybridizing these probes to metaphase cells with a del(5q) involving proximal or distal breakpoints within 5q31, we have narrowed the critical region to a small segment of 5q31 containing eight of the cosmids. In addition, we found that the five growth factor genes are excluded from this region. We have used dual colour FISH to determine the order of these cosmids, the order of the known genes mapped to 5q23-33 and the relationship of these genes to the critical region. To date, mutations of these genes in leukaemia cells have not been identified. The clinical features of myeloid diseases associated with a del(5q) are variable (RA 5q- syndrome v. AML); thus, once the involved gene is identified, it will be important to determine whether the same gene is involved in both types of myeloid disorders.
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PMID:Deletions of chromosome 5 in malignant myeloid disorders. 145 Nov 9

Friend virus induced erythroleukaemia can be conveniently divided into a first stage and a second stage. The first stage results from the mitogenic stimulation of EPO-R by gp55. In the second stage, multiple proviral integrations appear to result in further transformation of the SFFV infected erythroblast to a leukaemogenic state. The first stage results from EPO-R activation. After retroviral entry, mediated through an unknown receptor, and after cDNA synthesis and proviral integration, viral proteins are synthesized. Gp55 binds and activates EPO-R. A small but measurable amount of gp55-EPO-R complex is transported to the cell surface (Casadewall et al, 1991). In the presence of helper virus, the defective SFFV genome is packaged and released for subsequent rounds of infection. During the first stage, erythroblasts proliferate but are not tumorigenic. During the second stage of Friend disease, subsequent infections result in further proviral integrations in the host genome. Some of these integrations result in increased Spi-1 expression, whereas others result in decreased p53 expression. These events appear to account for the leukaemogenic properties of cells at this stage, 4-6 weeks after the initial SFFV infection. The interaction between EPO-R and gp55 persists at this later stage, although its contribution to the malignant phenotype of the MEL cells is not known. The sequence of events during stage 1 and stage 2 does not appear to have absolute requirements. Starting with IL-3 dependent immortalized Ba/F3 cells, which already have some unknown proliferative mutation (Mathey-Prevot et al, 1986), gp55 and EPO-R can subsequently be introduced, resulting in tumorigenicity (Li et al, 1990). The primary focus of this review has been the early mitogenic stage of Friend disease. Several concepts have emerged regarding the interaction between gp55 and EPO-R. The interaction between the polypeptides is highly specific, occurs in the extracytoplasmic regions and the transmembrane region of the polypeptides and occurs within the same cell, not via cell-cell contact. Both EPO and gp55 activate EPO-R, via different binding sites, resulting in increased cellular tyrosine kinase activity. The first stage of Friend disease is an example of how a non-oncogene bearing retrovirus can induce leukaemia. The env gene of the SFFV is not a classical oncogene. It does not appear to be derived from a normal cellular proto-oncogene. The interaction of gp55 and EPO-R therefore supports the "receptor mediated leukaemogenesis" hypothesis (McGrath and Weissman, 1978, 1979).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The interaction of the erythropoietin receptor and gp55. 145 Nov 11

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.
Leukemia 1992 Dec
PMID:Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2. 145 74

We report the biological characteristics of leukaemic blasts from two cases of acute leukaemia with an interstitial deletion of the long arm of chromosome 9 (9q-). Case 1 (FAB: M1) showed del(9)(q12q22) as the sole karyotypic anomaly, and case 2 (FAB: M1) presented del(9) (q12q22) in association with trisomy 10. In both cases, leukaemic blasts presented unique cytological features, such as prominent vacuoles on Giemsa staining, or strong localization of myeloperoxidase resembling 'pseudo-Chediak-Higashi' granules. Immunophenotyping of blasts revealed the biphenotypic expression of T-lymphoid/myeloid antigens (CD2, CD7/CD33) in addition to CD34. Neither T-cell receptor beta (TCRB), T-cell receptor gamma (TCRG) nor Ig heavy chain (IGH) genes were clonally rearranged. Furthermore, there was neither rearrangement nor expression of ABL, which is located at 9q34, indicating that the deletion involved bands centrometric to 9q34 did not induce the activation of ABL. DNA synthesis of the blasts was stimulated (stimulation index greater than 2.0) in the presence of interleukin (IL)-3, IL-4, granulocyte colony-stimulating factor or erythropoietin (Epo). IL-3 and IL-4 could also support the in vitro growth of leukaemic blast colonies, and the IL-3- or IL-4-dependent blast colony growth was synergistically enhanced by the addition of IL-6 or Epo. These observations imply that T-lymphoid/myeloid or pluripotent stem cells may be closely involved in the development of 9q- AML.
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PMID:Interstitial 9q deletion in T-lymphoid/myeloid biphenotypic leukaemia. 155 Jul 72

We have evaluated the feasibility of enhancing the cytotoxic effect of cytosine arabinoside (ara-C) on acute myeloid leukemia (AML) cells by increasing the proliferative activity with hematopoietic growth factors. Leukemic cells from 8 persons with AML were tested. Preincubation with interleukin (IL)-3 (5 U/ml) for 3 days increased DNA synthesis as measured by tritiated thymidine incorporation and Ki67 expression in cells from 7 out of 8 persons with AML. Leukemic cells preincubated with IL-1 (10 U/ml) or IL-3 (5 U/ml) were subsequently exposed to ara-C (3 micrograms/ml) for the final 24 h and the activity of ara-C against clonogenic acute myeloid leukemia cells was evaluated in terms of the inhibition of colony formation in semisolid media. The exposure to ara-C inhibits the proliferation of a higher proportion of clonogenic cells in culture pretreated with IL-3 than in control or cells pretreated with IL-1. The enhanced cytotoxic effect of ara-C in the cells pretreated with IL-3 correlated with increased formation of intracellular ara-CTP. IL-3-induced recruitment of quiescent blasts into the proliferative compartment will lead to increased formation of ara-CTP in the cells, which would result in an enhanced leukemia cell kill.
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PMID:Enhancement of the cytotoxicity of cytosine arabinoside by interleukin-3. 155

Recent work has demonstrated the ability of lymphoblastic leukemias of pre-B- and T-cell origin to grow in severe combined immunodeficient (SCID) mice with a pattern reminiscent of the human clinical disease. Here, we investigated the possibility of engrafting human myeloid leukemias using both established cell lines and primary patient material. Whereas the two growth factor-independent cell lines K562 and U937 grew aggressively and induced leukemia in these animals, three other myeloid cell lines which require interleukin 3 or granulocyte-macrophage colony-stimulating factor for continuous growth in vitro failed to induce disease. Primary bone marrow and peripheral blood cells from five out of seven patients with different types of myeloid leukemias (undifferentiated, megakaryoblastic, monoblastic and chronic myelogenous leukemia in blast crisis) induced patterns of leukemic infiltration that were distinct for each leukemia subtype. The diagnosis of leukemia in SCID mice was established by microscopic detection of myeloblasts in the bone marrow, peripheral blood and, in some instances, in extramedullary sites, including the central nervous system and gonads. The karyotype and phenotype of the blasts recovered from mouse tissues were identical to those of the original patient cells. Moreover, human specific ALU sequences were amplified from the bone marrow DNA by polymerase chain reaction. Despite their ability to grow in vivo by serial transfers in SCID mice, the leukemic cells recovered from mouse tissues could not be maintained in vitro, even in the presence of recombinant cytokines. Overall, these data indicate that the SCID mouse may represent a useful animal model for human myeloid leukemias and for the development of new pharmacological and molecular approaches to therapy.
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PMID:The severe combined immunodeficient (SCID) mouse as a model for human myeloid leukemias. 157 Jan 53


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