Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of human recombinant megakaryocyte growth and development factor (MGDF) (also known as thrombopoietin (TPO)), alone or in combination with other growth factors, on the proliferation and on the clonal growth of clonogenic progenitors from 24 acute myeloblastic leukemia (AML) patients were evaluated. A significant proliferative response to MGDF alone (proliferation index > 1.5) was observed in nine of 23 cases; the responding cases belonged to all FAB subtypes. However, the greatest response (proliferation index > 7) was found in one M6 and in one M7 case. MGDF also enhanced interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), c-kit ligand (KL) and FLT3 ligand (FL) stimulated blast cell proliferation. MGDF as a single factor induced or significantly enhanced colony formation by clonogenic precursor cells in 12 of 14 AML cases. MGDF strongly increased KL-induced leukemic colony growth in seven cases, whereas it only moderately enhanced IL-3- or GM-CSF-induced colony growth. The analysis of tyrosine phosphorylated protein(s) upon MGDF stimulation in fresh AML cells was also performed. The results demonstrated a band of approximately 90 kDa phosphorylated protein(s) upon MGDF stimulation in AML responsive cases, but not in unresponsive ones. Taken together the present findings suggest that, in a consistent proportion of AML cases, MGDF stimulates blast cell growth and induces tyrosine protein phosphorylation.
Leukemia 1997 Apr
PMID:Megakaryocyte growth and development factor (MGDF)-induced acute leukemia cell proliferation and clonal growth is associated with functional c-mpl. 909 94

Hematopoiesis is a complex process of regulated cellular proliferation and differentiation from the primitive stem cells to the final fully differentiated cell. The long and extensive search for a factor specifically regulating megakaryocytopoiesis led to the cloning of a hormone, here called thrombopoietin (TPO), that specifically promotes proliferation and differentiation of the megakaryocytic lineage. The availability of recombinant TPO and its imminent clinical use has made a more detailed understanding of its effects on hematopoietic cells more urgent. Normal megakaryocyto- and thrombopoiesis occurs predominantly in the bone marrow, a difficult organ to study in situ, particularly in humans, due to the low numbers of megakaryocytic progenitors and the consequent difficult isolation as pure populations. Thus, we developed an in vitro system which may allow us to address questions regarding the biology of TPO. The acute myeloid leukemia (AML)-derived cell lines HU-3, M-07e, M-MOK and TF-1 have absolute dependence on granulocyte-macrophage colony-stimulating factor (GM-CSF). We cultured these cells long term (> 6 months) in the continuous presence of TPO (omitting GM-CSF). TPO alone supported the maintenance and expansion of these sister cell lines, HU-3/TPO, M-07e/TPO, M-MOK/TPO and TF-1/TPO, that displayed somewhat longer doubling times, a larger cell size, and a higher percentage of polynucleated giant cells and slightly adherent cells than the corresponding countercultures grown with GM-CSF. In the absence of TPO the cells died quickly, within a few days; thus, the TPO-grown cell lines have an absolute dependence on this factor, but could all be switched back to growth with GM-CSF. In comparison with the GM-CSF-treated cells, the receptors for GM-CSF and interleukin-3 (IL-3) were down-regulated and the receptors for stem cell factor (SCF) and TPO were up-regulated in the TPO-exposed cells. A short-term proliferation assay showed a stronger response of the TPO-cell lines to erythropoietin, GM-CSF, IL-3, PIXY-321, SCF and TPO than the GM-CSF-cell lines. Flow cytometric analysis of the GM-CSF-and TPO-cultured lines displayed an up-regulation of the megakaryocytic surface markers CD41, CD42 and CD61, and a down-regulation of the erythroid marker glycophorin A in the latter cell lines, suggesting some differentiation along the megakaryocytic lineage. Thus, in long-term exposure, TPO appears to have both a proliferative and a differentiative effect on responsive cells. Under serum-deprived culture conditions, TPO acted as a survival factor on the TPO-cell lines. Taken together, these findings indicate that the TPO-dependent cell lines represent important biological reagents for further characterization of the biology of TPO and should also provide a great aid for future in vitro experiments aimed at elucidating megakaryocyto- and thrombopoiesis.
Leukemia 1997 Apr
PMID:Thrombopoietin supports the continuous growth of cytokine-dependent human leukemia cell lines. 909 95

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism of cytosine arabinoside (Ara-C) was comparatively analyzed in normal bone marrow mononuclear cells (NBMMC) from eight healthy volunteers and in leukemic blasts from 50 patients with acute myeloid leukemia (AML). Pretreatment with GM-CSF (100 U/ml) for 48 h resulted in a significant enhancement of DNA synthesis in both cell types: 21 of 35 AML specimens were found to be responsive to GM-CSF as defined by an increase of 3H-TdR incorporation into the DNA > 1.5-fold while NBMMC from normal donors were responsive in all cases. In GM-CSF responsive AML blasts, overall DNA polymerase and DNA polymerase alpha activity increased from a median of 84.4 to 96.1 and from 3.45 to 5.2 pmol/min x mg as compared to a median of 96.7 to 189.9 and 1.2 to 2.2 pmol/min x mg in NBMMC (P < 0.05). Median Ara-C-mediated inhibition of DNA synthesis was significantly more effective in AML blasts as compared to NBMMC (76.5 vs 55.0% at 0.05 microM and 99.0 vs 96.0% at 5.0 microM Ara-C, P < 0.01) but was not influenced by GM-CSF pretreatment. Similarly, intracellular Ara-CTP levels were higher in AML blasts as compared to NBMMC (median of 46.9 vs 18.7 at 1 microM, 167.8 vs 48.0 at 10 microM and 337.5 vs 59.5 ng/10(7) cells at 100 microM extracellular Ara-C, P < 0.01) but showed no enhancement in the presence of GM-CSF. Median deoxycytidine (DCK) and thymidine kinase (TK) activity were only slightly increased in AML blasts after GM-CSF priming. In contrast, NBMMC revealed a significant increase in TK activity after GM-CSF pretreatment (from a median of 1.9 to 3.6 pmol/min x mg, P = 0.039). At low; intermediate and high extracellular Ara-C concentrations GM-CSF pretreatment resulted in a significant enhancement of the 3H-Ara-C incorporation into the DNA in both GM-CSF responsive AML blasts and NBMMC (median of 1.3 to 2.1- and 1.4 to 1.6-fold, P < 0.05). GM-CSF non-responsive AML blasts showed no change in 3H-Ara-C incorporation into the DNA in response to GM-CSF at low Ara-C concentrations but significant increases at intermediate and high extracellular Ara-C concentrations (median increases of 1.63-fold at 1.06 microM with P = 0.01 and 1.37-fold at 10 microM extracellular Ara-C with P = 0.0+005). NBMMC revealed significantly lower GM-CSF-induced increases of the 3H-Ara-C incorporation into the DNA as compared to the effect of GM-CSF priming on DNA synthesis (median increases of 1.4 to 1.7-fold vs 2.6-fold, P < 0.05). These data reveal a different effect of GM-CSF priming on the metabolism of Ara-C in normal vs leukemic cells which may cause a preferential increase in the antileukemic cytotoxicity of Ara-C in the presence of GM-CSF.
Leukemia 1997 Apr
PMID:Differential effect of GM-CSF pretreatment on intracellular Ara-C metabolism in normal bone marrow mononuclear cells vs acute myeloid leukemia (AML) blasts. 909 97

The t(16;21)(p11;q22) translocation is a non-random chromosomal aberration observed in several types of human acute myeloblastic leukemia (AML), whereas the der(16)t(1;16) and chromosome rearrangements at 12q13 are frequently found in solid tumors. A novel cell line YNH-1 was established from peripheral blood cells of a 46-year-old male with AML (M1) carrying t(16;21) and t(1;16) translocations. YNH-1 has been maintained with a doubling time of 82 h for more than 20 months as a granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) dependent line. Morphologically YNH-1 cells were free-floating immature myeloblasts with lobulated nuclei and vacuoles in the cytoplasm. They were positive for myeloperoxidase but negative for alpha-naphthyl butylate esterase and chloroacetate esterase stainings. In surface marker analysis YNH-1 cells were positive for CD13, CD33 and CD34. Chromosomal analysis showed 46, XY, der(16)t(16;21)(p11;q22)t(1;16) (q12;q13), der(21)t(16;21)(p11;q22), der (6)t(6;12)(q13;q13), der(12)t(6;12)(q21;q13). These translocations were confirmed by fluorescence in situ hybridization (FISH) studies with the ERG-YAC clone and chromosome-specific DNA libraries. Both the FUS/ERG and ERG/FUS chimeric transcripts were identified by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Thus, YNH-1 could be a useful tool for elucidating the pathophysiology and molecular mechanism in AML with t(16;21),t(1;16) and 12q13 translocations.
Leukemia 1997 Apr
PMID:Establishment of a novel human acute myeloblastic leukemia cell line (YNH-1) with t(16;21), t(1;16) and 12q13 translocations. 909 2

Placebo-controlled and/or historically controlled trials have shown that granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance neutrophil recovery rates and occasionally reduce the rate and duration of infection. Some data appear to support an advantage with GM-CSF in reducing the incidence of fungal infections. Immunomodulation with cytokines such as interferon or interleukin-2 may prove to be of benefit in the management of acute leukemia when used in combination or sequence with chemotherapy.
Leukemia 1997 May
PMID:Use of cytokines in the treatment of acute lymphoblastic leukemia. 917 81

The ability of the physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and two novel vitamin D analogues, EB1089 and KH1060 to induce the differentiation of the U937 and HL-60 leukaemic cell lines was evaluated, alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Studies revealed that following 96 h treatment, the vitamin D derivatives inhibited the proliferation, and induced the differentiation of U937 and HL-60 cells in a dose-dependent manner, as determined by cell counts and nitroblue tetrazolium (NBT) reduction assays, respectively. EB1089 and KH1060 were found to be more effective than 1,25(OH)2D3 in exhibiting their antiproliferative and differentiative effects. In contrast, induction of leukaemic cell differentiation with 1 ng/ml GM-CSF after 96 h was less effective when compared with the vitamin D derivatives used individually. Fluorescence activated cell scanning (FACS) analyses indicated that the vitamin D derivatives readily induced the expression of the monocyte-associated cell surface antigen, CD14, and also the beta2-integrins, CD11b and CD18 in both cell lines after 48 h and 96 h treatment. The ability of EB1089 and KH1060 to induce these antigens was achieved with greater efficacy relative to the native hormone. When U937 and HL-60 cell cultures were cotreated for 48 h with the vitamin D compounds and GM-CSF and analysed by FACS, enhanced effects on CD14 and CD11b induction were observed compared to those of the compounds alone. These co-operative effects may occur as a consequence of molecular events which involve the transcription by vitamin D receptors (VDR) of genes required for the responsiveness of immature cells to factors such as GM-CSF, and place these and other related vitamin D analogues as potential therapeutic agents in the treatment of leukaemia.
Leukemia 1997 Jul
PMID:Interaction of vitamin D derivatives and granulocyte-macrophage colony-stimulating factor in leukaemic cell differentiation. 920 85

Grb2/Ash is composed of one SH2 and two SH3 domains and functions as an adapter linking tyrosine-kinase receptors and Ras in fibroblasts. The SH2 domain binds to tyrosine-phosphorylated proteins and the SH3 domain binds to protein containing proline-rich regions. However, the mechanisms of signal transduction through Grb2/Ash in hematopoietic cells are still unclear. By means of the binding experiments using the GST fusion protein including the full length Grb2/Ash, we have found that Shc and unidentified 130-kDa and 135-kDa proteins are associated with Grb2/Ash and that they are tyrosine-phosphorylated by treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) in a human leukemia cell line UT-7. We have purified the 130-kDa protein (pp 130) using GST-GRB2/Ash affinity column. The amino-acid sequence analysis showed that the pp130 was identical to the human c-cbl proto-oncogene product (c-Cbl). c-Cbl constitutively binds to the SH3 domain of Grb2/Ash both in vitro and in vivo but not to the SH2 domain of Grb2/Ash. Moreover, c-Cbl (pp 130) becomes tyrosine-phosphorylated rapidly and transiently depending on GM-CSF and EPO stimulation. However, we could not find the homologous regions with guanine nucleotide exchange factors or GTPase-activating proteins in the c-cbl gene. These findings strongly suggest that c-Cbl is implicated in the signal transduction of GM-CSF and EPO in hematopoietic cells, and c-Cbl and Grb2/Ash might also transduce a signal that is different from the signal leading to Ras regulation. Recently, we have shown that the proto-oncogene vav product (Vav) is also tyrosine-phosphorylated by treatment with GM-CSF and EPO and is constitutively associated with the SH3 domain of Grb2/Ash in UT-7. Another guanine nucleotide exchange factor Sos is also associated with Grb2/Ash in UT-7. It has been reported that Vav has guanine nucleotide exchange activity and activates Ras in vitro and in vivo. These data suggest that tyrosine kinases, the adapter Grb2/Ash, and the guanine nucleotide exchange factor Vav and Sos are members of a signaling pathway leading to Ras activation in hematopoietic cells.
Leukemia 1997 Apr
PMID:The signal transduction through Grb2/Ash in hematopoietic cells. 920 6

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

Idiopathic hypereosinophilic syndrome (HES) is a rare disease with no established effective therapy. It has been reported that interleukin-5 (IL-5) produced by helper T cells plays a major role in the proliferation of eosinophils. The nucleotide analogue 2-chlorodeoxyadenosine (2-CdA), which induces excellent clinical responses in hairy cell leukemia, is known to suppress helper T cells; therefore, we used 2-CdA, alone or in combination with cytarabine, to treat patients with idiopathic HES. 2-CdA alone and combined with cytarabine resulted in a rapid and sustained decrease in circulating eosinophils in two patients with idiopathic HES that was refractory to steroids, hydroxyurea and cytarabine. The efficacy of 2-CdA alone and combined with cytarabine exceeded by far that of cytarabine alone. However, reverse transcription-polymerase chain reaction (RT-PCR) did not show production of IL-5 or granulocyte-macrophage colony-stimulating factor mRNA in T cells as previously reported, and multiple cytokine receptors were found on eosinophils in idiopathic HES, suggesting that IL-5 may not be the sole cytokine involved in the regulation of idiopathic HES. The clinical efficacy of 2-CdA in idiopathic HES needs to be established on a large group of patients.
Leukemia 1997 Aug
PMID:2-Chlorodeoxyadenosine therapy for idiopathic hypereosinophilic syndrome. 926 99

A coculture system of a murine erythroblastic leukemia cell line (ELM-D) with its supportive stromal cell line (MS-5) was established. Long-term growth of ELM-D cells is strictly stroma cell dependent. Interaction between stem cell factor (SCF) and its receptor, c-kit, was demonstrated to be important for stroma cell-dependent growth by anti c-kit neutralizing monoclonal antibody (mAb) inhibition experiments. Significantly, soluble growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) or SCF of MS-5 stromal cells (MS-5 CM) could replace the requirement of stroma cells for a considerable period. However, ELM-D cells maintained in these growth factors underwent clonal extinction after 3-6 weeks unless contact with stroma was re-established. Furthermore, IL-3 or GM-CSF acted in a dominant manner in inducing cell death in the presence of stroma cells. Cells showing clonal extinction undergo programmed cell death and do not differentiate. These altered growth properties of ELM-D cells exposed to soluble growth factors or to stroma cells appear to be analogous to those described for T or B cells primed by antigen presenting cells and then grown in growth factors.
Leukemia 1997 Oct
PMID:The role of soluble growth factors in inducing transient growth and clonal extinction of stroma cell dependent erythroblastic leukemia cells. 932 97


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