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

A novel cell line SKNO-1 was established from the bone marrow cells of a 22-year-old male suffering from acute myeloblastic leukaemia (AML) M2 with t(8;21) whose disease became resistant to chemotherapy after acquisition of 17 monosomy. SKNO-1 has been maintained for more than 36 months as a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent line. Morphologically, SKNO-1 cells were myeloblasts somewhat matured. The cells grow in suspension with a doubling time of 48-72 h. The survival and growth of SKNO-1 cells was absolutely dependent on granulocyte-macrophage colony stimulating factor (GM-CSF). SKNO-1 cells possessed t(8;21) and monosomy 17 which were observed in original leukaemic cells. We confirmed that the AML1 gene, located on chromosome 21, was rearranged and the AML1-MTG8 fusion transcript was expressed in SKNO-1 cells. Over-expression and mutation of the p53 gene were also detected in SKNO-1. It is likely that alterations of AML1 or MTG8 gene and p53 gene contribute to a disease progression in this case. Since t(8;21) translocation is a common chromosome abnormality in AML, and inactivation of the p53 gene may play a crucial role in disease progression in AML, SKNO-1 would be a useful tool for analysing the molecular mechanisms in myeloid leukaemogenesis.
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PMID:Establishment of a myeloid leukaemic cell line (SKNO-1) from a patient with t(8;21) who acquired monosomy 17 during disease progression. 777 16

A large number of AML cases is reviewed in order to clarify biological characteristics of t(8;21) AML cells. The incidence of positivities for stem cell antigens, CD34 and HLA-DR, on blasts in t(8;21) AML is higher in comparison with those in other M2 or M3 categories. Frequent expression of CD34 and HLA-DR is indicative of the stem cell derivation of t(8;21) AML cells. The non-blastic leukemic cells in t(8;21) AML tend to lose the immature phenotype with discordant maturation such as low CD33 expression. Further, the blasts show frequent expression of the B-cell antigen, CD19, without other B-cell antigens and immunoglobulin gene rearrangements. AML cells with t(8;21) showed poorer response to granulocyte-macrophage colony-stimulating factor (GM-CSF) due to a decreased number of GM-CSF binding sites. The absence of monocytic differentiation in t(8;21) AML cells might represent the abnormal response to growth factors at the bifurcation stage of granulocyte and monocyte differentiation. Recently, breakpoint region genes for the 8;21 translocation in chromosome 8 and 21 have been isolated, 48-50 and have been named AML1 and ETO, respectively. The AML1 gene showed a strong homology with the Drosophila segmentation gene, runt, which is thought to be necessary for the Sex lethal gene expression. Since the GM-CSF receptor alpha chain gene locates in the pseudoautosomal region of the sex chromosome, the decrease of GM-CSF binding sites might be related to the AML1/ETO fusion gene expression. Further molecular genetic investigations of the breakpoint genes in the future are expected to clarify the unique biological events seen in this type of leukemia.
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PMID:Cellular characteristics of acute myeloblastic leukemia associated with t(8;21)(q22;q22). The Japanese Cooperative Group of Leukemia/Lymphoma. 804 46

AML1 is involved in the (8;21) translocation, associated with acute myelogenous leukemia (AML)-type M2, which results in the production of the AML1-ETO fusion protein: the amino-terminal 177 amino acids of AML1 and the carboxyl-terminal 575 amino acids of ETO. The mechanism by which AML1-ETO accomplishes leukemic transformation is unknown; however, AML1-ETO interferes with AML1 transactivation of such AML1 targets as the T-cell receptor beta enhancer and the granulocyte-macrophage colony-stimulating factor promoter. Herein, we explored the effect of AML1-ETO on regulation of a myeloid-specific AML1 target, the macrophage colony-stimulating factor (M-CSF) receptor promoter. We found that AML1-ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described. Truncation mutants within the ETO portion of AML1-ETO revealed the region of ETO necessary for the cooperativity between AML1 and AML1-ETO lies between amino acids 347 and 540. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8;21) and the promonocytic cell line U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8;21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls. The upregulation of M-CSF receptor expression by AML1-ETO may contribute to the development of a leukemic state in these patients.
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PMID:Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis. 887 34

Gene alterations accumulate during the progression of acute myelogenous leukemia (AML) to a malignant clone. Here, a new myeloid cell line, designated YSK-21, with the balanced t(8;21)(q22;q22) and the unbalanced der(1)t(1;17)(p36;q21), was established. YSK-21 grows well in a medium containing recombinant human granulocyte colony-stimulating factor (rhG-CSF), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), or interleukin-3 (rhIL-3). Molecular analysis using the reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) revealed that t(8;21)(q22;q22) resulted in an AML1-MTG8 fusion transcript. FISH and spectral karyotyping (SKY) in conjunction with G-banding analysis revealed a der(1)t(1;17)(p36;q21) chromosomal translocation, which appeared in the clone developed from the original leukemic cells. Molecular analysis of the TP73 gene on 1p36 and the TP53 gene revealed a deletion of one-allele in TP73 with partial demethylation of another allele in the initial clone of YSK, and a point mutation consisting of an A-->T substitution in codon 288 of the TP53 gene in the developed clone of YSK-21. YSK-21 cells, expressing aberrant AML1-MTG8, TP53, and TP73 protein molecules, may be useful for elucidating the pathophysiology of these aberrant proteins and for studying the der(1)t(1;17)(p36;q21) chromosomal translocation.
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PMID:Establishment of a cell line with AML1-MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia. 1155 Feb 87

The molecular pathways of normal myeloid differentiation, as well as the mechanisms by which oncogenes disrupt this process, remain poorly understood. A major limitation in approaching this problem has been the lack of suitable cell lines that exhibit normal, terminal, and synchronous differentiation in the absence of endogenous oncoproteins and in response to physiologic cytokines, and whose differentiation can be arrested by ectopically expressed human oncoproteins. This report describes clonal, granulocyte-macrophage colony-stimulating factor-dependent myeloid cell lines that exhibit these properties. The cell lines were established by conditional immortalization of primary murine marrow progenitors with an estrogen-regulated E2a/Pbx1-estrogen receptor fusion protein. Clones were identified that proliferated as immortalized blasts in the presence of estrogen, and that exhibited granulocytic, monocytic, or bipotential (granulocytic and monocytic) differentiation on estrogen withdrawal. Differentiation was normal and terminal as evidenced by morphology, cell surface markers, gene expression, and functional assays. The differentiation of the cells could be arrested by heterologous oncoproteins including AML1/ETO, PML/RARalpha, PLZF/RARalpha, Nup98/HoxA9, and other Hox proteins. Furthermore, the study examined the effects of cooperating oncoproteins such as Ras or Bcr/Abl, which allowed for both factor-independent proliferation and differentiation, or Bcl-2, which permitted factor-independent survival but not proliferation. These myeloid cell lines provide tools for examining the biochemical and genetic pathways that accompany normal differentiation as well as a system in which to dissect how other leukemic oncoproteins interfere with these pathways.
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PMID:Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins. 1158 24

Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are not common in acute myeloid leukemia (AML). Given that the RUNX1 transcription factor is the most common target for chromosomal translocations in acute leukemia, we asked if NF1 might be regulated by RUNX1. In reporter assays, RUNX1 activated the NF1 promoter and cooperated with C/EBPalpha and ETS2 to activate the NF1 promoter over 80-fold. Moreover, the t(8;21) fusion protein RUNX1-MTG8 (R/M), which represses RUNX1-regulated genes, actively repressed the NF1 promoter. R/M associated with the NF1 promoter in vivo and repressed endogenous NF1 gene expression. In addition, similar to loss of NF1, R/M expression enhanced the sensitivity of primary myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor. Our results indicate that the NF1 tumor suppressor gene is a direct transcriptional target of RUNX1 and the t(8;21) fusion protein, suggesting that suppression of NF1 expression contributes to the molecular pathogenesis of AML.
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PMID:Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. 1598 4