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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Total absence of CSF-1 in the op/op mouse leads to a profound and generalized deficiency of macrophages and to osteopetrosis subsequent to the absence of osteoclasts. These observations confirm that CSF-1 is a genuine regulator of macrophage and osteoclast formation in vivo. Further studies in affected animals have shown that the CSF-1 absence variably affects macrophage differentiation stages and different organ macrophage populations, and that functionally competent macrophages are produced in low numbers without CSF-1, presumably under the influence of GM-CSF and IL-3. The op/op mice have increased levels of both endogenous GM-CSF and IL-3, which apparently are not fully able to compensate for the absence of CSF-1. Macrophage deficiencies but not osteoclast deficiencies in the op/op mouse could be completely corrected by exogenous GM-CSF, while exogenous CSF-1 corrects both osteoclast and macrophage deficiencies, but only in those tissues which could be reached by CSF-1 from the circulation. Despite severe quantitative macrophage deficiencies, the op/op mice demonstrate normal in vivo phagocytosis and immune functions suggesting that CSF-1 dependent macrophages do not contribute significantly to those processes in vivo. On the other hand, the op/op mice demonstrate severe secondary deficiencies of TNF-alpha, IL-1 alpha, and G-CSF suggesting that major function of CSF-1 dependent macrophages is the release of monokines.
Leukemia 1993 Aug
PMID:In vivo role of macrophage growth factors as delineated using CSF-1 deficient op/op mouse. 836 Dec 13

Current evidence suggests that the most primitive of hematopoietic progenitors detectable in adult human marrow are cells that can give rise to clonogenic cells for > 5 weeks in vitro when co-cultured with certain stromal cells. Procedures developed to isolate these so-called long-term culture-initiating cells (LTC-IC) in highly purified form allow their separation from most other hematopoietic cells as well as from stromal cells and their precursors also present in the marrow. We have used such procedures in conjunction with the LTC system to identify specific growth factors that support human LTC-IC maintenance and differentiation and to make comparisons with effects on later events in hematopoiesis. In some studies, soluble growth factors were added exogenously to the study cultures. In others, marrow-derived fibroblasts were genetically engineered to allow increased levels of specific human growth factors to be endogenously produced. In both of these ways, the influence of granulocyte--macrophage colony-stimulating factor (GM-CSF), G-CSF, Interleukin-3 (IL-3), IL-6, and Steel factor were investigated. Increased provision of GM-CSF alone (or in combination with other factors) enhanced terminal cell differentiation (production of granulocytes and macrophages), although the same conditions had no influence on LTC-IC differentiation (production of clonogenic cells) or on LTC-IC maintenance. In contrast, G-CSF, IL-3 and IL-6 alone (and more so when combined) in the presence of feeders effectively enhanced LTC-IC differentiation and was less active on later stages of granulopoiesis. Provision of additional exogenous Steel factor also enhanced LTC-IC differentiation, although Steel factor alone, without feeders or other growth factors, did not support either the initial differentiation of LTC-IC into clonogenic cells or their subsequent differentiation into mature granulocytes and macrophages. No combination of exogenously added growth factors was found that enhanced LTC-IC maintenance over that achieved with primary marrow feeders. However, some murine fibroblasts (including those of SI/SI origin), as well as certain exogenous growth factors (including Steel factor), were able to substitute for feeders in this regard. These observations highlight the likelihood of redundancy in factors that can elicit similar biological responses at the earliest as well as later stages of hematopoietic cell development. Nevertheless, it appears that the responses of hematopoietic cells at different stages of differentiation to any particular factor may differ markedly and that the nature of any particular response is not yet predictable from a knowledge of effects on earlier or later cell types.
Leukemia 1993 Aug
PMID:Growth factor regulation of the maintenance and differentiation of human long-term culture-initiating cells (LTC-IC). 836 Dec 14

All-trans-retinoic (ATRA) treatment of patients with acute promyelocytic leukemia results in differentiation of the malignant cells and a high complete remission rate. ATRA treatment induced granulocytic differentiation in HL-60 cells as assessed by nitroblue tetrazolium (NBT) reduction, but had no effect on non-specific esterase (NSE) straining, as expected in cells maturing along the monocytic lineage. However, our results demonstrate that ATRA (0.1-10 microM) induces expression of the c-fms (monocyte colony-stimulating factor receptor) gene in HL-60 cells. This effect was detectable after 2 days and expression was maximal at 5 days. Similar results were obtained during treatment with cis-retinoic acid (CRA), hexamethylene bisacetamide (HMBA), or dimethyl sulfoxide (DMSO). The results also demonstrate that ATRA-induced c-fms expression is potentiated by exposure to tumor necrosis factor alpha (TNF alpha) or dibutyryl cyclic adenosine monophosphate (cAMP). The induction of c-fms transcripts by ATRA is associated with induction of M-CSF-binding ability, suggesting cell surface expression of the monocyte growth factor receptor. Our results indicate that retinoic acid can induce features of both monocytic and granulocytic differentiation in HL-60 cells.
Leukemia 1993 Mar
PMID:All-trans retinoic acid induces monocyte growth factor receptor (c-fms) gene expression in HL-60 leukemia cells. 844 50

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.
Leukemia 1996 Apr
PMID:Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. 861 33

Leukemia cell lines that do not proliferate in the absence of serum grow well when cultured with stromal cells. To study this growth dependence on stroma, we selected the M1 myeloblast clone, since its stroma dependence is reminiscent of that exhibited by hematopoietic stem cells. Conditioned medium form a stromal cell line, prepared under serum-free conditions, contained an activity that induced the proliferation of M1 cells and was therefore designated M1 myeloid activity (MMA). Among the various cytokines tested for MMA-like activity, only transforming growth factor-beta (TGF-beta) and macrophage colony-stimulating factor (M-CSF) were found to affect M1 cell survival, and the two cytokines acted synergistically to induce M1 cell growth. Antibodies to both TGF-beta and M-CSF abolished most, but not all, of the MMA in the medium conditioned by stromal cells, indicating that additional factors contribute to MMA. A subclone of M1 cells, M1/M2, selected in medium conditioned by stroma, was found to respond to stromal stimulation but was unable to proliferate in fetal calf serum (FCS). Neutralization experiments indicated that M1/2 cell growth depended mainly on M-CSF and also partially on TGF-beta. By contrast, the same neutralizing antibodies did not affect the ability of serum to support M1 cell growth. The molecules that promoted leukemia cell growth in serum seemed therefore to differ from those provided by stroma. This model system may offer novel information on the interactions of normal and leukemic hematopoietic cells with their stromal microenvironment.
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PMID:Interactions between leukemia cells and bone marrow stromal cells: stroma-supported growth vs. serum dependence and the roles of TGF-beta and M-CSF. 863 29

Following 200 cGy total body irradiation, 20-25% of CBA/Ca mice and their CBA/B and CBA/H sublines develop myeloid leukemia. To determine whether hematologic changes in vitro were detectable, long-term marrow cultures (LTBMCs) were established from the right and left hind limbs of 11 individual control and 11 CBA/B mice 100-114 days after 200 cGy total body irradiation. Individual cultures were studied weekly for cumulative production of nonadherent cells and colony-forming, hematopoietic progenitor cells. Control cultures produced significantly more nonadherent cells over 25 weeks in long-term marrow culture compared to those from irradiated (treated) mice. Permanent stromal cell lines were established from control and irradiated CBA/B mouse LTBMCs and clonal sublines were established. The stromal cell lines from LTBMCs of in vivo irradiated CBA/B mice had uniformly lower plating efficiencies, and only one formed a permanent clonal subline at 100-fold lower frequency compared to stromal cell lines from control mouse LTBMCs. The irradiation sensitivity of both uncloned and clonal sublines was similar by single-hit, multi-hit or by linear quadratic formula. Cocultivation of an IL-3 dependent hematopoietic progenitor cell line established from a control CBA/B, LTBMC with control of irradiated stromal cell lines derived from either a control (CC3) or the one successfully cloned in vivo irradiated (CT4) LTBMC, produced few cobblestone islands in the presence of IL-3. In contrast, formation of cobblestone islands in the presence of L cell-condition medium as a source of M-CSF was significantly greater, and these persisted for 21 days on both CC3 and CT4 stromal lines. The data provide evidence for irradiation induced changes in the bone marrow stromal cell compartment of CBA/B mice which persist and are detectable in vitro 6 months after explant of the cells to culture. These marrow stromal cell lines may provide valuable resources for analyzing the molecular biologic changes in the hematopoietic microenvironment during irradiation leukemogenesis.
Leukemia 1996 Mar
PMID:Effects of irradiation of CBA/CA mice on hematopoietic stem cells and stromal cells in long-term bone marrow cultures. 864 71

Stromal cell lines were established by irradiating adherent layers of bone marrow and spleen cells in Dexter-type long-term culture with X-rays. Some of these cell lines support myelopoiesis and/or B lymphopoiesis in vitro. Furthermore, the characteristics of these stromal cell lines were studied. Cytokine activity was detected in the conditioned media from all hematopoietic-supportive and non-supportive stromal cells. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed that the mRNAs of macrophage colony-stimulating factor and stem cell factor, but not that of Interleukin-3, were detectable in all the hematopoietic-supportive and non-supportive stromal cell lines. The transcripts of granulocyte colony-stimulating factor, interleukin-6, interleukin-7, and leukemia inhibitory factor were expressed in a wide variety of cell lines. Most stromal cell lines synthesized mRNA of c-mpl, the ligand of which stimulates megakaryopoiesis and thrombopoiesis. These observations indicate that the pattern of mRNA expression of cytokines is not correlated with the hematopoietic-supportive ability of stromal cell lines. There was a significant difference in the efficiency of adhesion of lineage marker-negative bone marrow cells to fibroblasts and stromal cell lines. This appears to be correlated with the hematopoietic-supportive ability of the stromal cell lines.
Leukemia 1996 May
PMID:Characterization of murine stromal cell clones established from bone marrow and spleen. 865 75

The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.
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PMID:Phase I trial of etoposide, carboplatin, and GM-CSF in extensive small-cell lung cancer: a Cancer and Leukemia Group B study (CALGB 8832). 902 Feb 83

The possible role of DNA methylation changes during several commitment steps of immature myeloid precursor cells toward functional, terminally differentiated phagocyte cells has previously been examined in the human myeloperoxidase (MPO) and macrophage colony-stimulating factor/c-fms genes using normal and transformed myeloid precursor cells. The human lysozyme (LZM) gene also provides a very useful model, because its protein synthesis is continuously increased during myelopoiesis and thus most abundant in mature phagocytes. Several shifts toward LZM gene demethylation coincide with upregulation of expression: activation of expression in myeloid precursor cells and in primary cells of acute myeloid leukemia (AML) was associated with demethylation at a CpG dinucleotide within the 5' flanking region; high-level expression in different types of normal mature phagocytic cells was associated with complete demethylation at two additional, intragenic CpG sites. Methylation changes occurring within the lysozyme gene could reflect transcriptional control of gene expression or maintenance of distinct maturation stages during phagocyte development. They correlate with maturational arrest and lysozyme gene expression in acute myeloid leukemias and may thus provide a genetic marker for the blocked differentiation of these neoplastic cells. Similar observations have been made for the MPO and c-fms genes.
Leukemia 1997 Mar
PMID:Cytosine methylation changes during normal hematopoiesis and in acute myeloid leukemia. 913 Jun 86

Chronic myelogenous leukemia is a neoplasm of pluripotent hematopoietic cells. Cytokines such as interleukin-3 and granulocyte-macrophage colony-stimulating factor regulate the growth and differentiation of hematopoietic precursors. These cytokines activate two distinct signals to the nucleus. One signal is through the Ras pathway, and the second involves activation of Jak2. We demonstrated that Bcr-Abl co-immunoprecipitates with and constitutively phosphorylates the common beta c chain of the interleukin-3 (IL-3) and granulocyte-macrophage-macrophage colony-stimulating factor (GM-CSF) receptors. Our data show that formation of this complex leads to the constitutive activation of Jak2. Previously, it has been demonstrated that Bcr-Abl interacts with Grb2 and Shc, which in turn activates the Ras pathway. Thus, Bcr-Abl can activate signalling through both pathways in a factor-independent fashion.
Leukemia 1997 Apr
PMID:P210 Bcr-Abl interacts with the interleukin-3 beta c subunit and constitutively activates Jak2. 920 14


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