Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myelosuppressive effects of human chemokines were evaluated in vitro on normal myeloid progenitors obtained from bone marrow and cord blood, on bone marrow progenitors from patients with acute or chronic leukemia, on proliferation of human factor-dependent cell line M07e, and in vivo on myelopoiesis in mice. Preincubation of human MIP-1 alpha, MIP-2 alpha, interleukin (IL)-8, platelet factor (PF) 4, monocyte chemotactic and activating factor (MCAF), and interferon-inducible protein-10 (IP-10) in an acetonitrile (ACN) solution significantly enhanced the specific activity of these chemokines for in vitro suppression of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells stimulated to proliferate with a colony stimulating factor plus steel factor (SLF). Combinations of any two of these ACN-treated chemokines synergized to suppress colony formation of CFU-GM, BFU-E, and CFU-GEMM at chemokine concentrations below that at which combinations of non-ACN treated chemokines are active. Cord blood progenitors, as previously reported, were in a slow or noncycling state and nonresponsive to inhibition by chemokines. However, after suspension culture with GM-CSF, IL-3, and SLF, they were placed into rapid cell cycle and were responsive to inhibition by ACN-treated chemokines. Low doses of these ACN-pretreated chemokines were active in vivo in suppressing absolute numbers and cycling status of femoral marrow CFU-GM, BFU-E, and CFU-GEMM in C3H/HeJ mice. Other chemokines, alone and in combination, including MIP-1 beta, MIP-2 beta, GRO-alpha NAP-2, and RANTES, were inactive in vitro and in vivo whether or not they were pretreated with ACN. While heterogeneity in responsiveness of CFU-GM from different patients with leukemia to suppression by ACN-treated chemokines was apparent, if the patients had CFU-GM responsive to one of the active chemokines these cells were responsive to the other active chemokines; if patient CFU-GM were not responsive to one of the chemokines, they were not responsive to the other active chemokines. M07e colony-forming cells were responsive to the growth-inhibiting effects of the active ACN-treated chemokines, alone and in combination, but these effects were rapidly reversible and sustained only by multiple daily additions of chemokines. These results should be of value in considering these chemokines for potential clinical use and for assessment of their mechanisms of action, alone and in combination.
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PMID:Human chemokines: enhancement of specific activity and effects in vitro on normal and leukemic progenitors and a factor-dependent cell line and in vivo in mice. 749 26

In vitro growth of primitive hematopoietic progenitors is severely impaired in the myelodysplastic syndromes (MDS). To determine if the c-kit ligand mast cell growth factor (MGF) can improve progenitor growth in MDS, we evaluated in vitro responsiveness of bone marrow progenitors from 25 patients to MGF and/or GM-CSF, interleukin-3 (IL-3) and PIXY 321, and examined the relationship between progenitor response and cellular expression of the c-kit receptor. MGF and erythropoietin gave rise to macroscopic colonies and dose-dependently increased CFU-GEMM and BFU-E up to 27-fold in 15 (60%) and 20 (80%) patients, respectively. Among 17 patients with absent growth in lymphocyte-conditioned media, MGF stimulated CFU-GEMM recovery in 59%, compared to 23% with PIXY 321, 12% with IL-3 and 8% with GM-CSF. Cytokine combinations did not augment recovery of erythropoietin-dependent progenitors above that achieved with MGF alone. MGF and/or IL-3 were comparatively weak stimulants of CFU-GM formation, whereas GM-CSF and PIXY in combination with MGF increased colony number 2- to 15-fold in 60 and 70% of patients, respectively, while preserving maturation competence as evidenced by colony composition and increased colony/cluster ratio. The stimulatory effects of MGF were observed in all morphologic categories of MDS except chronic myelomonocytic leukemia. A mononuclear cell population expressing the c-kit receptor was identified by flow cytometry in 57% of cases. Neither SR-1 reactivity nor cytogenetic pattern predicted progenitor response to MGF. These data indicate that MGF improves the colony-forming capacity of hematopoietic progenitors in MDS and is a potent co-stimulant of multipotent and committed progenitor recovery. The heterogeneity in MGF responsiveness implies an intrinsic defect in growth regulation not explained by cellular loss of c-kit display.
Leukemia 1994 May
PMID:Mast cell growth factor (c-kit ligand) restores growth of multipotent progenitors in myelodysplastic syndrome. 751 48

NK cell stimulatory factor, or IL-12 (NKSF/IL-12), is a heterodimeric cytokine produced by monocyte-macrophages, B cells, and possibly other accessory cell types. Although the major biologic effects of NKSF/IL-12 have been demonstrated on mature T and NK cells, in which it induces cytokine secretion, increased cytotoxicity, and proliferation, recent evidence in the murine system has suggested that NKSF/IL-12 may play a role in the differentiation of early lymphohematopoietic progenitor cells and thymocytes. In this paper, we have analyzed the effect of human rNKSF/IL-12 on the formation of colonies by highly enriched hematopoietic progenitor cells from human peripheral blood and bone marrow. At concentrations between 1 and 10 ng/ml, NKSF/IL-12 synergizes with a combination of steel factor and IL-3 to induce formation of mixed, erythroid, and myeloid colonies. Therefore, human NKSF/IL-12, like murine NKSF/IL-12, seems to belong to a small group of early acting cytokines, including IL-6, granulocyte-CSF, leukemia-inhibitory factor, and IL-11, which are able to synergize with steel factor and IL-3 to induce proliferation and differentiation of very early hematopoietic progenitor cells. However, in the presence of enriched preparations of NK cells cultured together with the progenitor cells, NKSF/IL-12 inhibits formation of hematopoietic colonies supported by IL-3 and granulocyte-macrophage CSF, by inducing production of IFN-gamma and TNF-alpha, two cytokines with synergistic inhibitory effects on hematopoietic colony formation. Because cell types that are able to produce NKSF/IL-12 are present in normal bone marrow and NKSF/IL-12 production in vivo and can be stimulated during bacterial or parasitic infection, it is possible that the direct stimulatory effect of NKSF/IL-12 on hematopoietic progenitor cells and the indirect inhibitory effect mediated by secondary cytokine production by lymphoid cells may play a role in the regulation of physiologic hematopoiesis and in its alterations during infection.
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PMID:Dual stimulatory and inhibitory effect of NK cell stimulatory factor/IL-12 on human hematopoiesis. 751 76

The growth of human leukemic cells in culture and in vivo is dependent upon the presence of hematopoietic growth factors. Most populations of human leukemic acute myeloblastic leukemia (AML) cells express c-Kit on their surface and respond to Kit ligand (KL) in culture. To determine if this interaction was of potential significance in vivo we used a mouse model system. 32D cells, a murine IL-3-dependent myeloid cell line, were rendered KL responsive by transfection of the murine c-Kit. After injection of 32D or 32D-Kit cells into syngeneic hosts, animals bearing 32D-Kit cells, but not 32D cells, became moribund and were killed. These animals had circulating leukemic blast cells, infiltration of bone marrow, spleen, brain, liver, lung, and kidney. Cells recovered from some of the animals continued to be dependent upon IL-3 or KL for growth while in other cases the cells were factor independent. This model illustrates that the constitutive expression of c-Kit enhances the leukemic potential of 32D cells. The model will be useful for studying the progression of leukemia in vivo and testing whether interruption of the interaction of Kit and KL can affect the growth of leukemic cells.
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PMID:c-KIT expression enhances the leukemogenic potential of 32D cells. 753 53

Cultures of differentiated melanocytes can readily be grown from the dissociated epidermis of neonatal mice, and immortal cell lines often develop from these. However, the first cells that grow and transiently dominate the cultures, while similar to melanocytes, are unpigmented. These have been shown to be precursors of melanocytes and may be termed melanoblasts. Under our previous standard culture conditions, involving the use of keratinocyte feeder cells, foetal calf serum, the phorbol ester 12-O-tetradecanoyl phorbol acetate (TPA) and cholera toxin, all the melanoblasts spontaneously differentiated to pigmented melanocytes within about 3 weeks. We now describe some factors affecting the proliferation and differentiation of diploid murine melanoblasts in the presence of serum. Murine stem cell factor/steel factor (SCF), basic fibroblast growth factor (bFGF) and murine leukaemia inhibitory factor/differentiation-inhibiting activity (LIF/DIA) all increased melanoblast numbers. SCF and LIF also slightly inhibited melanoblast differentiation, while cholera toxin and TPA promoted differentiation. Using some of these findings, and by regular replacement of keratinocyte or fibroblastoid feeder cells, we have established a clonal line of immortal murine melanoblasts, 'melb-a'. These cells express tyrosinase-related protein-2 but not, in general, tyrosinase. They can be induced to differentiate irreversibly to functional melanocytes (also proliferative and immortal) by plating in the absence of feeder cells. Thus a new immortal melanocyte line, 'melan-a2', has also been produced.
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PMID:A cloned, immortal line of murine melanoblasts inducible to differentiate to melanocytes. 754 May 32

Interleukin 7 (IL-7) stimulates proliferation of normal human and murine B cell precursor (BCP) cells in a distinct fashion, depending on the stage of maturation of the cells. For instance, the productive rearrangement of the immunoglobulin heavy chain gene has been demonstrated to be essential for the response of BCP cells to IL-7 as the single proliferation stimulus. IL-7 activates a receptor that consists of the IL-7R protein and the common gamma chain (gamma c). BCP acute lymphoblastic leukemia (BCP-ALL) cells variably respond to IL-7. Among 72 cases of BCP-ALL IL-7 activated DNA synthesis in 34. In four cases inhibition of DNA synthesis was seen. In the remaining 38 cases IL-7 exerted no effects. We determined whether this heterogeneity in IL-7 response could be correlated with parameters that could influence the IL-7 response. Firstly we show that, in contrast to the murine BCP cells, the IL-7 response of human BCP-ALL cells did not correlate with the status of IgH chain gene rearrangement and expression, nor with the rearrangement of IgL chain genes. Subsequently, it is demonstrated that IL-7R protein and transcripts as well as gamma c transcripts are equally present in the IL-7 responsive and nonresponsive BCP-ALL samples, indicating that the defective expression of these chains could not be held responsible for IL-7 response failures. Finally, we observed that kit ligand (KL), known to synergize with IL-7 in the most primitive stages of normal B cell development, did not enhance the IL-7 responses of BCP-ALL cells.
Leukemia 1995 Jun
PMID:Heterogeneity of proliferative responses of human B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells to interleukin 7 (IL-7): no correlation with immunoglobulin gene status and expression of IL-7 receptor or IL-2/IL-4/IL-7 receptor common gamma chain genes. 759 67

2H3 subline of rat basophilic leukemia (RBL-2H3) cells are mast cell analogs that lack responsiveness to nonimmunologic stimuli such as compound 48/80 and substance P. To determine if fibroblasts can influence this responsiveness, RBL-2H3 cells were cocultured with confluent monolayers of mouse 3T3 fibroblasts and assayed for secretagogue-induced histamine release. After 1 wk in coculture, RBL-2H3 cells began to respond to compound 48/80. Responsiveness reached a maximum at 2 wk in coculture and remained at this level for an additional 2 wk. Histamine release was specific, noncytotoxic, dose-dependent, and occurred even in the absence of extracellular Ca2+. No soluble factor from 3T3 cells was found that induced these alterations. Moreover, neither recombinant rat or mouse steel factor, at concentrations up to 250 ng/ml, was able to alter RBL-2H3 cell reactivity to compound 48/80. By 2 wk in coculture, RBL-2H3 cells also became responsive to substance P, although no changes in histamine content, Alcian blue+/safranin- staining or type of serine protease were detected. These results show that 3T3 fibroblasts cause an alteration in the functional repertoire of RBL-2H3 cells and that soluble steel factor cannot duplicate the effect.
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PMID:Mouse 3T3 fibroblasts induce rat basophilic leukemia (RBL-2H3) cells to acquire responsiveness to compound 48/80. 767 78

We have investigated the stimulative effects of mast cell growth factor (MGF) in primary acute myeloid leukemia (AML) in vitro. MGF stimulated DNA synthesis of purified leukemic blasts in eight out of 10 cases and colony formation in four cases in serum-free (SF) culture. MGF synergized with interleukin-3 (IL-3; four out of 10 cases), granulocyte-macrophage colony-stimulating factor (GM-CSF; three out of 10 cases), granulocyte colony-stimulating factor (G-CSF; six out of 10 cases), macrophage colony-stimulating factor (M-CSF; one out of 10 cases) and erythropoietin (EPO; one out of 10 cases) when added to culture in combination. Synergistic effects of MGF in combination with other CSFs were also seen in the colony assay. Antibodies against GM-CSF, M-CSF, G-CSF, and IL-6 did not inhibit the MGF response, suggesting that the stimulative effect of MGF was not mediated through autocrine release of those cytokines. Cell recovery data in liquid cultures that contained MGF, IL-3, or MGF + IL-3, indicated that both MGF and IL-3 augmented the maintenance of clonogenic cells as compared to nonsupplemented cultures, but the effect of the combination of IL-3 + MGF did not show synergy. In contrast, activation of DNA synthesis by MGF was abrogated in the presence of tumor necrosis factor (TNF; four out of 10 cases) and interleukin-4 (IL-4; two out of 10 cases). Fluorescence-activated cell sorting (FACS) analysis with anti c-kit antibodies revealed MGF receptor expression in eight out of nine cases, often in a subpopulation of the cells. Scatchard analysis of MGF receptors in two cases indicated the presence of 1460 and 41,500 (mean) binding sites, respectively, of high affinity (Kd 40-160 pmol/l). The MGF dose-response curve in the presence of IL-3 or GM-CSF resulted in a higher plateau of DNA synthesis, however no shift in the dose response was apparent. The respective reciprocal dose response relations to GM-CSF, IL-3, or G-CSF were similarly elevated when MGF was added. MGF did not alter IL-3 and GM-CSF receptor expression, nor did IL-3, GM-CSF, G-CSF, TNF, or IL-4 influence MGF binding to AML cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1993 Mar
PMID:Effects of mast cell growth factor on acute myeloid leukemia cells in vitro: effects of combinations with other cytokines. 768 Apr 1

To determine whether a requirement for exogenous growth factors (GFs) for survival and proliferation could identify cases of AML which would respond best to GFs, singly and in combination, primary AML bone marrow samples were grown in suspension. Samples were classified as GF-dependent (61%), or GF-independent (39%) based on maintenance of Ki67+ cell number (proliferating cells) in the absence of exogenous GFs. GF-dependent samples had significant proliferative responses to steel factor (SF), GM-CSF and IL-3; mean Ki67+ cell number increased by 4.1-, 3.3-, and 5.2-fold, respectively. Significant stimulation was not seen for GF-independent cases; several were inhibited by exogenous GFs. SF was additive or synergistic with GM-CSF or IL-3 among GF-dependent cases; however, combinations were no more effective than single cytokines among the GF-independent group. GM-CSF plus IL-3 or the hybrid protein PIXY 321 did not increase the mean Ki67 ratio compared to the individual cytokines for any population. Flow cytometric determination of GF receptor expression was less predictive of GF response than was survival and proliferation in the absence of GFs. Suspension cultures in the absence of GFs can select patients most likely to benefit from therapeutic strategies using GFs for cell cycle recruitment.
Leukemia 1994 Nov
PMID:Identification of growth factor-responsive acute myelogenous leukemia based on factor-dependence for survival and proliferation. 796 31

The mouse proto-oncogene Pim-1, which encodes two cytoplasmic serine-threonine-specific protein kinases, is frequently activated by proviral insertion in murine leukemia virus-induced hematopoietic tumors. Transgenic mice overexpressing Pim-1 show a low incidence of spontaneous T cell lymphomas, whereas null mutant mice lack an obvious phenotype. We have analyzed the early B lymphoid compartment from both null mutant and E mu-Pim-1 transgenic mice. The level of Pim-1 expression appears to be a determining factor in the ability of these cells to respond to the growth factors interleukin 7 (IL-7) and SF (steel factor). The impaired response in null mutant mice could be rescued by introduction of a functional Pim-1 transgene. Moreover, overexpression of Pim-1 facilitates the derivation of primitive lymphoid cell lines that are dependent on combined stimulation with IL-7 and SF or insulin-like growth factor 1. These results for the first time identify the involvement of Pim-1 in a normal cellular function, as an important regulator of early B lymphopoiesis in mice.
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PMID:Pim-1 levels determine the size of early B lymphoid compartments in bone marrow. 822 13


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