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 effectiveness of endogenous or exogenously administered colony-stimulating factors may be modulated by the presence of hematopoietic inhibitory molecules. Cytotoxic therapy may result in the induction of hematopoietic inhibitors contributing to prolonged myelosuppression, whereas preventing the induction of such inhibitors may accelerate multilineage recovery. Lisofylline [LSF; (R)-1-(5-hydroxyhexyl)-3,7, dimethyl-xanthine], inhibits the signaling and/or release of certain hematopoietic inhibitory molecules such as tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, transforming growth factor beta, and IFN-gamma. Treatment of murine bone marrow cells with the cytotoxic agent 5-fluorouracil (5-FU) results in the release of a nondialyzable inhibitor of progenitor (colony-forming unit-granulocyte macrophage; CFU-GM) proliferation. When murine bone marrow cells were treated with 5-FU plus LSF, release of this inhibitor of CFU-GM proliferation was blocked. Neutralizing antibody and Western blot analysis indicated that the inhibitor was TGF-beta. We tested the effect of LSF (100 mg/kg i.p., b.i.d.) on multilineage regeneration after high-dose 5-FU or thiotepa treatment in BALB/c mice. In 4 of 5 experiments, LSF significantly accelerated neutrophil recovery (P < or = 0.05, Wilcoxon paired-signed test). In addition, platelet, reticulocyte, and CFU-GM regeneration were significantly accelerated in mice treated with LSF compared to control mice (P < or = 0.05). LSF had no significant effects on the ability of 5-FU to kill hematopoietic progenitor cells, nor did LSF stimulate or inhibit proliferation of CFU-GM. LSF had no effect on chemotherapy-induced killing of tumor cells in vitro, nor on the antitumor activity of 5-FU or thiotepa in BALB/c mice implanted with P388 leukemia cells. Inhibition of hematopoietic inhibitor release may accelerate multilineage recovery after cytotoxic therapy and, as such, may represent an alternative or additional therapy to the use of positively acting lineage specific colony-stimulating factors.
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PMID:Lisofylline inhibits transforming growth factor beta release and enhances trilineage hematopoietic recovery after 5-fluorouracil treatment in mice. 854 48

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

Human monoblastic leukemia U937 cells are induced to differentiate into monocytes and macrophages by various agents. We have shown that 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-9), an inhibitor of myosin light chain kinase, induces differentiation of monocytoid leukemia cell lines U937 and THP-1 but not of myeloblastic leukemic ML-1 cell or erythroleukemia K562 cells. In the present study, we further analyzed the effect of ML-9 in comparison with that of 1 alpha, 25-dihydroxyvitamin D3 (VD3) a typical inducer of monocytic differentiation. ML-9 induced nitroblue tetrazolium (NBT)-reducing activity of U937 cell more rapidly than VD3: This differentiation marker was induced significantly after incubation with ML-9 and VD3 for 4 hours and 1 day, respectively. ML-9 also induced alpha-naphthyl acetate esterase (ANAE) activity, another monocytic differentiation marker, more rapidly than VD3. The maximum levels of these markers induced by ML-9 were comparable to those induced by VD3, but after removal of ML-9 from the medium by washing the cells, the expressions of theses markers decreased within 4 hours and reached basal levels in 1 day, indicating that ML-9's induction of expression of differentiation-associated phenotypes was reversible. The growth inhibition of U937 cells by ML-9 was also reversible. Similar effects were observed in another line of human monoblastic cells, THP-1. ML-9 had little or no effect on the morphology of U937 cells but increased the expression of monocyte-macrophage lineage-associated surface antigen, CD14, to some extent. Irreversible terminal differentiation induced by VD3 is associated with down regulation of the expression of c-myc and upregulation of the expression of c-fos and c-jun, but ML-9 did not affect the expression of these oncogenes appreciably. ML-9-induced differentiation was also reversible when the cells were cultured with cultured with ML-9 plus an anti-cancer drug such as 1-beta-D-arabino-furanosylcytosine or daunomycin. it became irreversible, however, upon simultaneous treatment with dexamethasone and transforming growth factor-beta 1 (TGF-beta 1), which did not induce differentiation of U937 cells but caused growth arrest of the cells in the G0/G1 phase of the cell cycle. These results suggest that ML-9 should be useful for studying the mechanisms of monocytic differentiation.
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PMID:Reversible differentiation of human monoblastic leukemia U937 cells by ML-9, an inhibitor of myosin light chain kinase. 863 23

Towards dissecting the regulation of terminal differentiation, including growth arrest and apoptosis, myeloid differentiation primary response (MyD) genes, induced in the absence of de novo protein synthesis following induction of M1 myeloblastic leukemia cells for terminal differentiation have been isolated. MyD118 was one of the novel MyD genes cloned, subsequently observed also to be a primary response gene to TGF-beta, which induces M1 cells for growth arrest and apoptosis uncoupled from differentiation. The MyD118 encoded protein was observed to be remarkably similar to the protein encoded by Gadd45, a growth arrest and DNA damage induced gene, regulated in part by the tumor suppressor p53. Though evidence has accumulated that MyD118 functions as an important modulator of negative growth control both in hematopoietic and non-hematopoietic cells, its mechanism of action is unknown. To better understand the role(s) of MyD118 in negative growth control, we have analysed the expression and biological characteristics of the MyD118 protein, compared to the Gadd45 protein, in distinct pathways of growth arrest and apoptosis, including p53 dependent and independent pathways either coupled or uncoupled from differentiation. It is shown that MyD118 and Gadd45 differentially accumulated upon induction of distinct pathways of growth arrest and apoptosis; notably, MyD118, but not Gadd45, was induced by TGF-beta, whereas Gadd45, but not MyD118, was induced by activating wild type (wt) p53 function. It is also shown that MyD118 is a nuclear protein, which regardless of the pathway induced, predominantly localized within the cell nucleus, and interacted with the DNA replication and repair protein PCNA and the cyclin dependent kinase inhibitor P21WAF1/CIP1. MyD118 also modestly stimulated DNA repair in vitro. All of these characteristics were shared with Gadd45. Finally, it is demonstrated that MyD118, Gadd45 and p21 synergized in the suppression of colony formation by NIH3T3 cells. Taken together, these findings demonstrate that MyD118 and Gadd45 are representative of a new protein family that share remarkable functional similarities in the control of distinct pathways of negative growth, including the suppression of cellular growth and programmed cell death.
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PMID:The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. 870 May 17

There is increasing evidence that the supportive cells (stromal cells) in nearly all organs containing cellular self-renewal systems are involved in carcinogenesis. One body of evidence specific to irradiation leukemogenesis documents the role of irradiated murine stromal cells in the cell biologic changes associated with evolution of leukemia in cocultivated, nonirradiated stem cells. Stem cell phenotypic changes that have been documented include upregulation of cell surface c-fms, downregulation of growth requirement for obligatory growth factors, and the appearance of novel transcripts detected by differential display. A second body of evidence documents the potential role of stromal cells functioning as biologic tumor promoters through their release of reactive oxygen species (ROS), and production of altered adhesion molecules or growth factors during the chronic response to chemical or physical carcinogens. These molecular biologic mechanisms, potentially operative in stromal cells, can block apoptosis and induce DNA strand breaks in closely associated self-renewing stem cells. In an in vivo model of irradiation effects on lung stromal cells, we have irradiated the lungs of control C57BL/6J mice or other mice with orthotopic Lewis lung tumors and shown that TGF-beta release is increased following irradiation. The TGF-beta increase by irradiation may specifically be inhibited by administering an inhalation plasmid liposome mixture containing a transgene for human manganese superoxide dismutase prior to irradiation. An appreciation of the role of stromal cells in leukemogenesis and carcinogenesis may also be very relevant to the design of new therapeutic strategies for treatment of cancer, particularly since current strategies focus on eradication of stem cell transformants and do not rigorously address the persistence of surviving stromal cells.
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PMID:Stromal cell involvement in leukemogenesis and carcinogenesis. 872 6

Human T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia (ATL), and the virus-encoded trans-activator, Tax, plays an important role in T cell transformation. In the HTLV-1 long terminal repeat (LTR)-Tax transgenic mouse model, Tax expression causes fibroblastic tumors. A tumor-derived cell line (B line) obtained from an explant of a Tax-transformed tumor, was established. This line expresses high levels of many cytokines as a consequence of Tax activation. However, the tumors are not immunogenic when transplanted into syngeneic mice. Because B line cells do not express the immunogenic cytokine interferon-gamma (IFN-gamma), a replication-defective adenoviral vector was used to deliver the IFN-gamma gene to tumor cells. The recombinant IFN-gamma adenovirus (IFN-gamma/Ad) can efficiently infect B line cells, resulting in high levels of IFN-gamma expression and secretion. Local secretion of IFN-gamma from B line cells caused both CD(4+)- and CD(8+)-positive T cell infiltration, and completely inhibited local tumor development in transplanted mice. Immunization with these cells significantly delayed tumor development after subsequent challenges of parental tumor cells. Expression of IFN-gamma in B cells also partially inhibited the highly expressed immune suppressive cytokine, transforming growth factor-beta 1 (TGF-beta 1). This system provides us with a valuable tumor immune therapy model to evaluate the effects of cytokines in induction or inhibition of specific antitumor immunity.
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PMID:Adenovirus-mediated interferon-gamma transfer inhibits growth of transplanted HTLV-1 Tax tumors in mice. 880 Jul 41

p16 INK4A and/or p15 INK4B genes are frequently deleted in leukemias and other cancers. We have established a novel pre-B acute lymphoblastic leukemia (ALL) cell line (JKB2) with a chromosomal translocation between 9p2l and 14q32, on which p16INK4A/p15INK4B and heavy chain immunoglobulin (Ig) genes, respectively, are located. Homozygous deletions of P16INK4A/p15INK4B genes in JKB2 cells were confirmed by polymerase chain reaction, and their protein products were not detectable by Western blotting. Therefore JKB2 is the first example of an immunoglobulin heavy chain translocation associated with deletions of these genes. In JKB2 cells, cyclin-dependent kinase(CDK)4 and CDK6 formed complexes with cyclin D, due to the lack of p16, triggering phosphorylation of retinoblastoma protein (pRB) and continuous cell proliferation. Moreover, the growth of JKB2 cells was partially inhibited by TGF beta or IL-7, accompanied by decreased CDK4 and CDK6 expression, increased p2l and p27 expression, decreased p27 binding to CDK4/CDK6, and increased binding of p27 to CDK2. In addition, IL-7 both inhibited proliferation and induced differentiation of JKB2 cells. These studies suggest that a t(9;14)(p21;q32) chromosomal translocation can result in deletion of both p16 INK4A and p15 INK4B genes in pre-B ALL, and that the JKB2 cell line therefore provides a model for the study of leukemogenesis related to abnormalities in chromosome 9p2l. Moreover, they suggest that TGF-beta can, suppress JKB2 cell growth in a p15-independent mechanism.
Leukemia 1996 Oct
PMID:A novel pre-B acute lymphoblastic leukemia cell line with chromosomal translocation between p16(INK4A)/p15(INK4B) tumor suppressor and immunoglobulin heavy chain genes: TGFbeta/IL-7 inhibitory signaling mechanism. 884 92

We examined the effect of diffusible factors generated during the culture of the KM102 stromal cell line as well as in long-term bone marrow culture (LTBMC) on K562 leukemia cells, with respect to proliferation of clonogenic cells as well as total cells, and compared it with the effect on normal myeloid progenitors (CFU-GM). Proliferation of K562 cells plated in diffusion chambers was inhibited by coculture for 3-5 days in the fluid phase of stromal cell cultures or stromal cell-conditioned medium (CM), while CFU-GM proliferation was not inhibited under the same culture conditions. The inhibitory action was not attributed to the exhaustion of nutrients or growth promoting factors such as stem cell factor. These findings suggest that bone marrow stromal cells secrete diffusible molecule(s) which exert a preferential inhibitory effect on K562 leukemic cells vs. normal CFU-GM. Neutralization with antibodies against hematopoiesis-inhibiting cytokines such as TGF-beta 1, IFN-gamma, MIP-1 alpha and IL-4 which were detected in stromal cell-CM, failed to abrogate the inhibitory effect of KM102-CM on K562 cells. IL-1, TNF-alpha, IFN-alpha and lipopolysaccharides, known as stimulators of various cytokines from stromal cells, could not enhance the inhibitory activity. Further characterization of the factors may have implications for the treatment of leukemias.
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PMID:Preferential inhibitory effect of soluble factor(s) in human bone marrow stromal cells on proliferation of K562 leukemia cells versus normal myeloid progenitor cells. 893 34

We investigated the cell kinetic effects of retinoic acid (RA) and the functional interaction between RA and TGF-beta on normal human bone marrow progenitor cells (CD34+). Cell cycle progression throughout the first three consecutive cell cycles and alterations in cell kinetic responses were measured using the BrdU-Hoechst quenching technique. RA stimulates the IL-3-induced growth by additionally recruiting quiescent stem and progenitor cells out of the G0/G1-phase and by increasing the cell cycle traverse rate. In contrast, TGF-beta addition resulted in a significant decrease in the number of proliferating cells. Simultaneous addition of RA and TGF-beta resulted in a stronger inhibition compared to addition of TGF-beta alone. Preincubation experiments further showed that RA is capable of sensitizing the progenitors to the inhibitory action of TGF-beta: the inhibitory effect of TGF-beta was significantly increased when cells were pretreated with RA. These data show that, in combination with IL-3, RA additionally stimulates quiescent bone marrow progenitors in a simultaneous way, and that it increases sensitivity of the progenitors to the inhibitory action of TGF-beta. The combination of RA and TGF-beta on normal and leukemic hematopoiesis has to be further investigated, since this combination may possibly provide additional therapeutic benefit.
Leukemia 1996 Dec
PMID:The combined effects of all-trans retinoic acid and TGF-beta on the initial proliferation of normal human bone marrow progenitor cells. 894 34

Thrombopoietin (TPO) is a major regulator of megakaryocytopoiesis both in vivo and in vitro. TPO initiates its biological effects by binding to the c-MPL receptor, which is a member of the hematopoietin receptor superfamily. To define the regulation of the MPL receptor, six continuous human leukemia cell lines with megakaryocytic properties were treated with the phorbol ester 12-myristate 13-acetate (PMA), TPO and transforming growth factor (TGF)-beta 1, a cytokine known to possess inhibitory effects. We used Northern blotting and flow cytometry analysis to determine MPL mRNA and protein levels. An increase of MPL mRNA and protein expression was observed in 2/6 PMA-exposed cell lines. There is no evidence from this study that TPO or TGF-beta 1 cause any decrease or increase in MPL expression. MPL upregulation triggered by PMA was accompanied by signs of induced differentiation such as increase in CD41, CD42 and CD61 expression, increase in cell size and cessation of proliferation. These data demonstrate that MPL can be upregulated in differentiating megakaryocytic cells via stimulation of protein kinase C, the intracellular target of PMA and a key kinase in one of the second messenger signal transduction pathways. These findings further the understanding of the regulation of this molecule, a cytokine receptor that, together with its ligand TPO, appears to represent a crucial element in megakaryocytopoiesis.
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PMID:Phorbol ester PMA induces expression of the thrombopoietin receptor MPL in leukemia cells. 904 71


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