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 DNA hypomethylating agent 5-aza-2'-deoxycytidine was able to induce irreversible terminal differentiation of the human monoblastic leukemia cell line U-937, when administered at a concentration of 0.1 microM every 12 hours for six times (72 hours). Differentiation occurred after removal of the drug, as shown by the gradual appearance of morphological, cytochemical, phenotypical, and functional cell maturation, along with the loss of the proliferative potential. Adherence to the plastic surface, a further marker of monocytic differentiation, was observed in long-term cultures of treated cells. Molecular events induced by 5-aza-2'-deoxycytidine included a decrease in DNA methylation, along with a dramatic, permanent reduction in the levels of c-myc transcripts; both these events were detectable early (24 to 48 hours) after the start of drug administration. A stable increase in c-fos and c-fms mRNAs, regarded as molecular markers of monocytic differentiation, was observed only after the end of treatment, in concomitance with the appearance of differentiation markers. The latency between early and late effects elicited by 5-aza-2'-deoxycytidine in U-937 cells suggests that the drug, presumably through DNA hypomethylation, is able to promote 'competence' to differentiate, via the activation of the regulatory program(s) needed for a monoblast to maturate, rather than directly inducing the expression of differentiation-specific genes. The temporal order of events described renders the present model suitable for the study of the human monocytic developmental program and of the molecular regulatory steps entailing differentiation by 5-aza-2'-deoxycytidine.
Leukemia 1993 May
PMID:Effects of 5-aza-2'-deoxycytidine on differentiation and oncogene expression in the human monoblastic leukemia cell line U-937. 768 59

Gene expression of various cytokine receptors in CD7+ acute lymphoblastic leukemia (ALL) cells in relation to responsiveness to these cytokines was examined by reverse transcription polymerase chain reaction and Northern blot studies. Leukemic cells from all of seven CD7+ ALL patients examined fulfilled the criteria for ALL according to the FAB classification; surface CD3 was absent in all of these patients, while cytoplasmic CD3 and/or CD3 epsilon mRNA were found in all of them. Samples from six of the seven patients at initial disease expressed the granulocyte colony-stimulating factor receptor (G-CSFR) gene. Leukemic cells with G-CSFR transcripts from one patient at initial disease showed growth response to G-CSF in vitro, and those from two other patients became responsive to G-CSF at relapse. Neither in vitro nor in vivo myeloid differentiation was observed in any samples that responded to G-CSF. Interleukin 3R alpha (IL-3R alpha) gene was expressed in samples from one patient at initial disease and from two patients at relapse. GM-CSFR beta gene mRNA was detected in two patients with IL-3R alpha mRNA. Our results show that the leukemic cells in these CD7+ ALL patients frequently expressed G-CSFR as a functional property, thus calling attention to the appropriate clinical application of G-CSF for ALL patients.
Leukemia 1993 Aug
PMID:Frequent gene expression of granulocyte colony-stimulating factor (G-CSF) receptor in CD7+ surface CD3- acute lymphoblastic leukaemia. 768 38

The KIT proto-oncogene encodes a tyrosine kinase receptor which plays a critical role in haemopoiesis. We have screened genomic DNA from bone marrow mononuclear cells of 46 patients with myelodysplasia (MDS) for mutations/deletions of exons 6, 13, 17, and 21 of the KIT gene (stem cell factor receptor) using polymerase chain reaction (PCR), polyacrylamide gel electrophoresis, and autoradiography to detect single-stranded conformational polymorphisms (SSCP). These exons include positions analogous to those mutated in the FMS gene (colony-stimulating factor-1 receptor) in myelodysplastic syndrome (MDS) and mutated/deleted in the Dominant White Spotting mouse (W locus) which results in macrocytic anaemia. Two different gel running conditions were used for each exon. Polymorphisms were identified only at 4 degrees C in exon 17 (three out of 44 MDS samples and two of 21 DNA samples from normal subjects), and in the non-coding region of exon 21 (five out of 34 MDS samples and seven out of 19 normals). Direct sequencing identified a G to A base change at nucleotide 3169 within exon 21, and a C to T change at position 2415 in exon 17. No conformational changes suggestive of mutations or deletions have been found to date, although we cannot rule out low frequency clonal abnormalities undetectable by our method, which has a sensitivity in our hands of approximately 5%. Polymorphisms occur frequently in the KIT gene. Together with this study, a total of five have been described.
Leukemia 1993 Nov
PMID:Two new polymorphisms but no mutations of the KIT gene in patients with myelodysplasia at positions corresponding to human FMS and murine W locus mutational hot spots. 769 8

The c-fms gene encodes the receptor for the macrophage colony-stimulating factor, which plays a key role in the proliferation and differentiation of cells of the myelomonocytic lineage. In order to study the effects of overexpression of the macrophage colony-stimulating factor receptor in hematopoietic cells, a Harvey sarcoma virus-derived retroviral vector containing the murine c-fms cDNA was pseudotyped with Friend murine leukemia virus and inoculated into newborn DBA/2 mice. This viral complex induced monoclonal or oligoclonal leukemias with a shorter latency than that for Friend murine leukemia virus alone. Unexpectedly, 60% of the integrated fms proviruses had deletions at the 5' end of the c-fms gene. Sequence analysis of seven mutant proviruses indicated that the deletions always included the c-fms ligand binding domain and either occurred within the c-fms sequences, leaving the fms open reading frame unchanged, or joined VL30 sequences located at the 5' end of the parental retroviral vector to internal c-fms sequences, resulting in truncated fms proteins devoid of the canonical signal peptide. In contrast to all tyrosine kinase receptors transduced in retroviruses, no helper gag- or env-derived sequences were fused to the rearranged fms sequences. Viral supernatants isolated from hematopoietic tumors with viruses with deletions were able to transform NIH 3T3 cells as efficiently as parental fms virus, indicating that deletions resulted in constitutive activation of the c-fms gene. These oncogenic variants differ from those transduced in the Suzan McDonough strain of feline sarcoma viruses (L. Donner, L. A. Fedele, C. F. Garon, S. J. Anderson, and C. J. Sherr, J. Virol. 41:489-500, 1982). The high rate of c-fms rearrangement and its relevance in the occurrence of hematopoietic tumors are discussed.
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PMID:Isolation of new oncogenic forms of the murine c-fms gene. 774 7

The FMS proto-oncogene encodes a polypeptide growth factor receptor expressed on the cell surface of monocytes and B lymphocytes within the haematological system. Mutations of the FMS gene at codons 301 and 969 have been detected in a number of haematological disorders. Mutations at these codons are thought to be important in the pathogenesis of leukaemia in cells expressing a mutant receptor. Following our finding that the colony stimulating factor-1 receptor (CSF-1R) was expressed on B cells, we have assessed DNA from 17 patients with B-cell chronic lymphocytic leukaemia (CLL), 15 with acute lymphoblastic leukaemias (ALL), two samples from patients with B-cell non-Hodgkin's lymphoma (B-NHL), and 20 haematologically normal individuals for the presence of C-terminal mutations of the FMS gene. Using single stranded conformational polymorphism analysis (SSCP), a single band shift was detected resulting from a nucleotide insertion at codon 965 in the DNA isolated from a patient with B-NHL. These results indicate that mutations of the FMS gene in this region are rare in B-cell malignancy but may contribute to the pathogenesis of leukaemias and lymphomas in a small subset of patients. However, the presence of other mutations not detected using this type of analysis cannot be excluded.
Leukemia 1995 Jan
PMID:A C-terminal FMS mutation in a patient with B-cell malignancy. 784 11

Hemopoietic growth factors have been implicated in the pathogenesis of some myeloid leukemias when the cells acquire the autocrine capacity to produce a relevant growth factor. We report transformation of the immortalized cell line FDC-P1 by overexpression of murine c-fms, the receptor for macrophage colony-stimulating factor (M-CSF). Three types of cell lines were obtained following expression of c-fms in FDC-P1 cells. The first type of cell line (FD-c-fms) was dependent on stimulation by M-CSF to induce cell proliferation and also underwent limited monocytic/macrophage differentiation in response to M-CSF. The second type of cell line (FD-c-fmsi) was able to proliferate in serum-containing cultures without stimulation by exogenous hemopoietic regulators. Stimulation of the FD-c-fmsi cell lines with M-CSF suppressed proliferation compared to cultures of unstimulated cells and induced monocytic/macrophage differentiation. The third type of cell line (FD-c-fms) was autonomous, failed to differentiate in response to M-CSF and secreted M-CSF into the culture medium, suggesting an autocrine mechanism of transformation. All three types of cell lines demonstrated varying degrees of suppression of cell proliferation when stimulated by the combination of M-CSF and GM-CSF. The data indicate that transformation of c-fms expressing cells results in a variety of phenotypes with dissociation of M-CSF induced proliferation and differentiation in different cell lines.
Leukemia 1995 Jan
PMID:Overexpression of C-FMS in the myeloid cell line FDC-P1 induces transformation that dissociates M-CSF-induced proliferation and differentiation. 784 31

Patients who have received cytotoxic therapy for primary neoplastic disease are at an increased risk of developing secondary (therapy-related) acute myeloid leukaemia (AML) or myelodysplasia (MDS). RAS and FMS mutations have been observed in patients with AML and MDS. It has been suggested that the mutational status within these genes may be predictive of early secondary leukaemic disease. In this study we have screened 50 haematologically normal patients in complete remission from childhood acute lymphoblastic leukaemia (ALL) for activating point mutations in the RAS and FMS proto-oncogenes. Such patients may be considered at risk of therapy-related disease. Codons 12, 13 and 61 were screened in RAS and codon 969 in FMS using the polymerase chain reaction (PCR) followed by oligonucleotide hybridization (ONH). Three of the 50 patients (6%) were found to harbour N12 RAS mutations. One of these three patients (2%) had both a N12 RAS and FMS 969 mutation. Upon sequencing the RAS mutations, substitutions of serine, cysteine and aspartic acid for glycine were identified. The FMS 969 mutation was also confirmed, by sequencing, as a histidine substitution. RAS mutations were not detected in presentation samples indicating that these lesions have been somatically acquired presumably subsequent to cytotoxic therapy for the primary disease. Continued follow-up of these patients may indicate a role for these mutations in the development of secondary malignancies.
Leukemia 1995 Mar
PMID:RAS and FMS mutations following cytotoxic therapy for childhood acute lymphoblastic leukaemia. 756 28

The receptor for macrophage colony stimulating factor (CSF-1), the c-fms gene product, is a key determinant in the differentiation of monocytic phagocytes. Dissection of the human and mouse c-fms proximal promoters revealed opposing roles for nuclear protooncogenes in the transcriptional regulation of this gene. On the one hand, c-ets-1, c-ets-2, and the macrophage-specific factor PU.1, but not the ets-factor PEA3, trans-activated the c-fms proximal promoter. On the other hand c-myb repressed proximal promoter activity in macrophages and blocked the action of c-ets-1 and c-ets-2. Basal c-fms promoter activity was almost undetectable in the M1 leukaemia line, which expressed high levels of c-myb, but was activated as cells differentiated in response to leukemia inhibitory factor and expressed c-fms mRNA. The repressor function of c-myb depended on the COOH-terminal domain of the protein. We propose that ets-factors are necessary for the tissue-restricted expression of c-fms and that c-myb acts to ensure correct temporal expression of c-fms during myeloid differentiation.
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PMID:Opposing actions of c-ets/PU.1 and c-myb protooncogene products in regulating the macrophage-specific promoters of the human and mouse colony-stimulating factor-1 receptor (c-fms) genes. 796 3

Density-dependent cell proliferation and cluster formation are growth phenotypes frequently associated with leukemia cells. The secretion of autocrine growth factor, such as granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 1 (IL-1), has been implicated as one possible mechanism in leukemogenesis. In many cases, however, leukemia cells do not appear to produce autocrine growth stimulators. J6-1 is an established human myeloid leukemia cell line that exhibits both density-dependent and cluster-forming growth characteristics. The effect of direct cell-cell contact on J6-1 cell proliferation was investigated. We have isolated from J6-1 cells a membrane-bound factor (designated as MAF-J6-1) that promoted the colony formation by both J6-1 cells and mouse bone marrow CFU-GM. The growth-promoting activity of MAF-J6-1 can be neutralized by either anti-macrophage-CSF (M-CSF or CSF-1) or anti-MAF-J6-1 monoclonal antibodies (MAb), suggesting that MAF-J6-1 is related to M-CSF. Using an immunoblot analysis with anti-MAF-J6-1 MAb, the MW of this membrane-associated factor was estimated to be 80 kDa. Both antibodies also induced a modest growth inhibition on J6-1 cells in vitro. Similarly, addition of exogenous recombinant human M-CSF augmented the colony formation by J6-1 cells, an effect also neutralized by both antibodies. Using an in situ hybridization technique, J6-1 cells were found to express a high level of c-fms proto-oncogene, which encodes the receptor for the M-CSF. Taken together, our results suggest that the membrane-bound MAF-J6-1 promote J6-1 cell proliferation and cluster formation through a 'juxtacrine' mechanism.
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PMID:Enhancement of J6-1 human leukemic cell proliferation by cell-cell contact: role of an M-CSF-like membrane-associated growth factor MAF-J6-1. 796 11

The granulocyte colony-stimulating factor receptor (G-CSFR) was overexpressed in WEHI-3B D+ myelomonocytic leukemia cells by the transfection of an expression plasmid containing the murine G-CSFR cDNA. Two different forms of the G-CSFR were observed in these cells by western blotting. Metabolic labeling and cell surface labeling demonstrated that the majority of the G-CSFR exists in a non-mature form and is presumably present in the cytoplasm as a 115-kDa protein. A relatively small portion of the G-CSFR is present as the fully mature form on the cell surface as a 150-kDa protein; this form of the G-CSFR binds to granulocyte colony-stimulating factor (G-CSF). Both the mature and non-mature forms of the G-CSFR appear to be N-glycosylated, as determined by glycanase digestion and inhibition of glycosylation by tunicamycin. Glycosylation of the G-CSFR may be of importance for the transport of the receptor to the cell surface.
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PMID:Evidence for the glycosylation of the granulocyte colony-stimulating factor receptor. 799 29


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