Leukaemia Research Fund annual guest lecture 1990. Genetics lesions in preleukaemia.
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Chromosome Aberrations↗
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Results for “Genes, fms”
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Retroviral v-myc infection of primary fetal liver cells: transformation of monocytes in vitro.
Oncogenes carried by retroviruses can alter the growth properties of many cell types. We examined the molecular mechanism by which a retrovirus containing one or a combination of oncogenes can transform and immortalize hematopoietic cells. Murine fetal liver cells were used as an enriched source of early hematopoietic cell progenitors; the cells were infected with a series of recombinant murine retroviruses capable of expressing the avian v-myc, v-H-ras and v-raf oncogenes. Three factor-independent cell lines were obtained: FL-ras/myc, FL-J2 (v-raf/v-myc) and FL-myc, a unique cell line generated using a single oncogene. Cytochemical, morphologic and phenotypic analyses indicated that these cell lines were of the monocyte lineage. Southern and Northern blot analyses revealed that the three cell lines had integrated viral DNA and were expressing the mRNA transcripts corresponding to these viral oncogenes. To examine the mechanism of factor independence, supernatants from these cell lines were tested for CSF-1 activity. Supernatants from FL-myc and FL-ras/myc cells were shown to contain CSF-1 activity and Northern blot analysis of the three cell lines revealed the presence of mRNA transcripts for the CSF-1 and c-fms genes. It is possible that the growth factor independence of these cell lines is related to the development of autocrine-induced proliferation.
Animals↗
The FGF-related oncogene, K-FGF, maps to human chromosome region 11q13, possibly near int-2.
The protein encoded in a novel human oncogene isolated by transfection of Kaposi's sarcoma DNA is a growth factor with significant homology to basic and acidic FGFs. The genomic structure of this oncogene (designated K-FGF), as originally isolated, carried DNA rearrangements upstream and downstream of the coding region. The normally discontinuous sequence upstream of the K-FGF coding region derived from the 3' end of the c-fms gene and thus originated from human chromosome 5. In order to determine the normal chromosomal location of the K-FGF gene and of the DNA sequences adjacent to its 3' end, we have correlated the presence of these sequences with retention of specific human chromosome regions in rodent-human somatic cell hybrids. These experiments mapped the K-FGF gene to human chromosome region 11q13----11q23, and in situ hybridization localized it more precisely to region 11q13 near int-2, which also belongs to the FGF family. The sequence downstream of the gene in transfectants and discontinuous with K-FGF in normal human DNA derives from chromosome region 12p12----12q13, possibly near the int-1 locus.
Chromosome Mapping↗
Binding of membrane-anchored macrophage colony-stimulating factor (M-CSF) to its receptor mediates specific adhesion between stromal cells and M-CSF receptor-bearing hematopoietic cells.
To explore the biologic significance of the membrane-anchored form of macrophage colony-stimulating factor (M-CSF), we examined whether interaction between membrane-bound M-CSF and its receptor mediates intercellular adhesion as well as cell proliferation and differentiation. Human M-CSF receptors were expressed on a murine interleukin-2 (IL-3)-dependent cell line, FDC-P2, by DNA transfection with the c-fms gene (FDC-P2-MCSFR). A human bone marrow-derived stromal cell line, KM102, was used in the cell adhesion assay. The expression of membrane-bound M-CSF on KM102 cells was demonstrated by flow cytometry and immunoblot analysis. After the incubation of parent and transformed FDC-P2 cells on confluent KM102 cells, nonadherent cells were removed and the cells attached to KM102 cells were examined microscopically. Almost all parent FDC-P2 cells were nonadherent, whereas a significant number of FDC-P2-MCSFR cells bound to KM102 cells. The addition of anti-M-CSF or anti-M-CSF receptor neutralizing antibodies dose-dependently inhibited the binding of [3H]-thymidine-labeled FDC-P2-MCSFR cells to KM102 cells. An excess amount of M-CSF also inhibited the binding. On the other hand, the addition of antibodies against some representative adhesion molecules (vitronectin receptor, Pgp-1/CD44, and VLA-4) did not inhibit the adhesion between FDC-P2-MCSFR cells and KM102 cells. These results support the idea that membrane-anchored M-CSF and its receptor may function as mediators of cell-cell adhesion.
Animals↗
[Myelodysplastic syndromes--clinical and biological features].
The myelodysplastic syndromes comprise a heterogeneous group of hematopoietic disorders characterized by peripheral cytopenia, and ineffective and dysplastic hematopoiesis. Patients are predominantly aged, and often develop acute non-lymphocytic leukemia. Bone marrow failure, notably infection and bleeding, is the most common cause of death. Our understanding of the biology of the myelodysplastic syndromes is limited and thus reduces the efficacy and specificity of therapeutic intervention. Available evidence, however, suggests that the myelodysplastic syndromes arise from hematopoietic stem cells. The emergence and progression of the myelodysplastic clone have been reviewed in the light of the multistep theory of human carcinogenesis.
Cell Death↗
Molecular genetic aspects of myelodysplastic syndromes.
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Chromosome Inversion↗
The myelodysplastic syndromes.
The myelodysplastic syndromes (MDSs) are a group of haematological disorders found predominantly in the elderly, and are defined by morphological abnormalities of the three cell lines. None of the abnormalities is specific for MDS but, when combined with active or hyperactive haemopoiesis and refractory cytopenia in an elderly person, they suggest the diagnosis. The French-American-British co-operative group divided MDSs into five types: refractory anaemia; refractory anaemia with ring sideroblasts; refractory anaemia with excess of blasts; refractory anaemia with excess of blasts in transformation; and chronic myelomonocytic leukaemia. The classification was based on the number of blasts in the bone marrow, dysplastic features in one or more cell lines, ringed sideroblasts, blasts in the peripheral blood, Auer rods in the granulocyte precursors and absolute monocytosis. MDS can be a primary condition and of unknown aetiology or develop secondary to the action of a known agent such as an alkylating agent, chemical or recombinant human granulocyte colony-stimulating factor. The pathogenesis of MDS is thought to be a multi-step process which begins with a somatic mutation in the pluripotential stem cell, is irreversibly altered and acquires a survival advantage. The abnormal clone expands at the expense of normal haemopoiesis and undergoes further genetic change to give a progressively more malignant phenotype. Present theories of the development of MDS are speculative but further research could cast light on the development of other haematological disorders.
Anemia, Refractory↗
Genetic aberrations in the development and subsequent progression of myelodysplastic syndrome.
We performed longitudinal analyses of chromosomes and studied the configuration of NRAS, TP53, NF1, and cFMS genes in 70 patients with myelodysplastic syndrome(MDS). The NRAS mutations were detected in 6 patients(9%) at codons 12 or 13. The TP53 mutations were found in 10 patients(14%) in exons 4 through 8. Longitudinal studies revealed that the NRAS mutation was a late-appearing event, while the TP53 mutations were detectable at the presentation of MDS. No patients had both NRAS and TP53 mutations, simultaneously. NF1 and cFMS genes showed any mutational event among these 70 patients. Patients with a TP53 mutation had a significantly shorter survival time than those with an NRAS mutation or those without NRAS or TP53 mutation. However, patients who showed an NRAS mutation had a shorter survival time once the mutation emerged, similar to that of patients with a TP53 mutation.
Adolescent↗
[Molecular abnormalities and clonality in myelodysplastic syndromes].
Few genes have a proven role in the pathogenesis of myelodysplastic syndromes (MDS). The most common abnormalities involve the RAS genes, most notably the N-RAS gene, and are present in 10% of cases at diagnosis and in 30% to 40% during the course of the disease. Mutations of the p53 are found in 5% to 10% of cases. Mutations of the cFMS genes are less common, abnormalities of the NF1 genes seem to occur only in children, and abnormalities of the RB genes are exceedingly rare. A few instances of t(5;12) or t(3;21) translocation have been demonstrated, and their study has provided evidence that the TEL, EVI1, MDS1, and AML1 genes are involved in some cases of MDS. The presence in MDS of recurrent chromosome 7, 5q, and 20q deletions suggests that these chromosomal segments may bear tumor suppressor genes involved in MDS. The gene(s) involved remain(s) to be identified. Clonality studies have shown that stem cell involvement usually occurs at the myeloid level and that normal multipotent stem cells persist in many patients with MDS. This opens up the promising possibility that transplantation of autologous multipotent stem cells may be an effective therapeutic approach.
Adult↗
Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes.
A 5' untranslated exon of the human CSF-1 receptor gene (c-fms) is separated by a 26 kb intron from the 32 kb receptor coding sequences. Nucleotide sequence analysis of cloned genomic DNA revealed that the 3' end of the PDGF receptor gene is located less than 0.5 kb upstream from this exon. Similarities in chromosomal localization, organization, and encoded amino acid sequences suggest that the genes encoding the CSF-1 and PDGF receptors arose through duplication. The as yet unidentified c-fms promoter/enhancer sequences may be confined to the nucleotides separating the two genes or could potentially lie within the PDGF receptor gene itself.
Amino Acid Sequence↗
Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene.
We have isolated and sequenced part of a new gene of the tyrosine kinase family. This gene, called FLT3, has strong sequence similarities with members of a group of genes encoding growth factor receptors: FMS, KIT, and PDGFR. We have localized the human FLT3 gene to chromosome 13, band q12, and its mouse homolog to chromosome 5, region G.
Amino Acid Sequence↗
Lack of involvement of the c-fms and N-myc genes by chromosomal translocation t(2;5)(p23;q35) common to malignancies with features of so-called malignant histiocytosis.
We report the molecular, cytogenetic, and immunologic characterization of three hematologic malignancies that contained characteristic t(2;5) chromosomal translocations. The clinicopathologic features in all three cases fit the disease spectrum of so-called malignant histiocytosis (MH). All cases expressed activation antigens including Ki-1 (CD 30), but no lineage-restricted pattern of cellular antigen expression was observed. Cell lines SUP-M2 and SU-DHL-1 established from two of the cases showed rearranged beta T-cell receptor (beta TCR) genes nonproductive of full-length beta TCR mRNA and therefore not helpful in unequivocal establishment of lineage derivation. The common cytogenetic feature was a reciprocal translocation between chromosomes 2 and 5, involving bands 2p23 and 5q35 near the reported chromosomal locations of the N-myc and c-fms genes, respectively. Normal-sized and truncated c-fms RNAs were observed in both cell lines, whereas no N-myc transcripts were detected. Sequence analysis of the truncated fms RNA showed that it consisted of the 3' half of the c-fms mRNA, but its derivation was not the result of a structural alteration of the c-fms gene. Our studies show that the t(2;5) does not involve the N-myc and c-fms protooncogenes and that this cytogenetic abnormality may be characteristic of a subset of primitive malignancies with an indeterminate lineage but with clinicopathologic features of so-called MH.
Adult↗
Truncation of peptide deformylase reduces the growth rate and stabilizes solvent production in Clostridium beijerinckii NCIMB 8052.
The wild-type strain of Clostridium beijerinckii NCIMB 8052 tends to degenerate (i.e., lose the ability to form solvents) after prolonged periods of laboratory culture. Several Tn1545 mutants of this organism showing enhanced long-term stability of solvent production were isolated. Four of them harbor identical insertions within the fms (def) gene, which encodes peptide deformylase (PDF). The C. beijerinckii fms gene product contains four diagnostic residues involved in the Zn2+ coordination and catalysis found in all PDFs, but it is unusually small, because it lacks the dispensable disordered C-terminal domain. Unlike previously characterized PDFs from Escherichia coli and Thermus thermophilus, the C. beijerinckii PDF can apparently tolerate N-terminal truncation. The Tn1545 insertion in the mutants is at a site corresponding to residue 15 of the predicted gene product. This probably removes 23 N-terminal residues from PDF, leaving a 116-residue protein. The mutant PDF retains at least partial function, and it complements an fms(Ts) strain of E. coli. Northern hybridizations indicate that the mutant gene is actively transcribed in C. beijerinckii. This can only occur from a previously unsuspected, outwardly directed promoter located close to the right end of Tn1545. The Tn1545 insertion in fms causes a reduction in the growth rate of C. beijerinckii, and, associated with this, the bacteria display an enhanced stability of solvent production. The latter phenotype can be mimicked in the wild type by reducing the growth rate. Therefore, the observed amelioration of degeneration in the mutants is probably due to their reduced growth rates.
Amidohydrolases↗
Expression and genomic configuration of GM-CSF, IL-3, M-CSF receptor (C-FMS), early growth response gene-1 (EGR-1) and M-CSF genes in primary myelodysplastic syndromes.
Peripheral blood mononuclear cells from seventeen patients with primary myelodysplastic syndromes (MDS) in advanced stage were enriched for blasts and tested for (1) karyotype, (2) genomic configuration and (3) expression of IL-3, GM-CSF, FMS and EGR-1 genes which are all located on the long arm of chromosome 5. The expression of the M-CSF gene, that has been recently reassigned to the short arm of chromosome 1 (lp), was also investigated. Aims of the study were to (1) assess the potential role of the expression of these genes in the maintenance and expansion of the neoplastic clones and (2) search for constitutional losses or rearrangements of one allele followed by a deletion of the second allele of the same genes in the leukemic cells. The latter issue was investigated by comparing, in 8 cases, constitutive DNA from skin fibroblasts with leukemic DNA. Eleven of the 17 patients had abnormal karyotypes. The M-CSF gene was expressed in 6 cases and the FMS and the EGR-1 genes were expressed in 2 of the latter cases. An autocrine mechanism of growth could be hypothesized only for the 2 patients whose cells expressed both the M-CSF and FMS genes. No germline changes or rearrangements were observed in any of the genes studied. Thus, deregulation of genes encoding for certain hemopoietic growth factors or receptors does not seem to represent a major mechanism of MDS progression.
Aged↗
Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family.
A new human gene encoding a receptor-type tyrosine kinase was isolated by a weak cross-hybridization with v-ros oncogene. A cDNA of about 7.7 kb carried a 4.2 kb open reading frame, and the predicted amino acid sequence of 1338 residues contained extracellular, transmembrane and tyrosine kinase domains. Although its extracellular domain is approximately 220 amino acids longer than those of the products of the fms family, i.e. c-fms, c-kit and platelet-derived growth factor receptor genes, the overall structure including cysteine motifs in its extracellular domain and a long peptide insertion in its tyrosine kinase domain indicates that this new gene is closely related to the fms family. Consequently, the gene was designated as flt (fms-like tyrosine kinase) gene. The expression of the flt gene was strongly suppressed in most of the tumor cell lines examined so far, whereas this mRNA was expressed in a variety of normal tissues of adult rat.
Amino Acid Sequence↗
"Replacement" of COOH-terminal truncation of v-fms with c-fms sequences markedly reduces transformation potential.
Protooncogenes when transduced by retroviruses may undergo structural modifications that render their gene products oncogenic. The c-fms gene encodes a transmembrane protein with tyrosine kinase activity that is very similar or identical to the receptor for the monocyte-macrophage colony-stimulating factor. Its transforming homologue (v-fms) in the Susan McDonough strain feline sarcoma virus causes fibrosarcomas in cats. Molecular cloning and sequence analysis of the cDNA that encodes the cytoplasmic domain of the human c-fms gene shows that the product of the transduced viral homologue, v-fms, is truncated at the COOH-terminal end. The COOH-terminal 40 amino acids of the c-fms gene product are replaced in the v-fms gene product by 11 amino acids encoded by the retroviral genome. Hybrid v-fms/c-fms genes, in which either the entire cytoplasmic domain or the COOH-terminal coding sequences of the v-fms gene were replaced by the corresponding segments of the c-fms gene, had a reduced ability to transform fibroblasts despite a high level of encoded protein on the cell surface. These data indicate that the COOH-terminal modifications contribute to the transforming potential of the v-fms viral oncogene product.
Amino Acid Sequence↗
C-FMS dependent HL-60 cell differentiation and regulation of RB gene expression.
The dependence of induced myelomonocytic cell differentiation, and regulation of the RB tumor suppressor gene during this process, on the c-fms gene product, the CSF-1 lymphokine receptor, was determined in HL-60 promyelocytic leukemia cells. Adding a monoclonal antibody with specificity for the c-fms gene product to cells treated with various inducers of myelomonocytic or macrophage differentiation, including retinoic acid and 1,25-dihydroxy vitamin D3, inhibited the rate of differentiation. During the period of inducer treatment usually preceding onset of differentiation, longer periods of antibody exposure caused greater inhibition of differentiation. In a stable HL-60 transfectant overexpressing the CSF-1 receptor at the cell surface due to a constitutively driven c-fms trans gene, the rate of differentiation was enhanced compared to the wild type cell, consistent with a positive regulatory role for the CSF-1 receptor. The anti-fms antibody caused much less inhibition of differentiation in the transfectants than in wild type cells, consistent with a larger number of receptors causing reduced sensitivity. During the induced metabolic cascade leading to differentiation, the typical early down regulation of RB gene expression was inhibited by the antibody. The antibody itself caused an increase in RB expression per cell, which offset the decrease normally caused by differentiation inducers (1,25-dihydroxy vitamin D3 and retinoic acid). The changes in RB expression preceded changes in the RB protein to the hypophosphorylated state. Most of the RB protein in proliferating cells was phosphorylated and no significant accumulation of hypophosphorylated RB protein occurred until after onset of G0 arrest. Thus the metabolic cascade leading to myelomonocytic differentiation of HL-60 cells appears to be driven by a function of the c-fms protein. Inhibiting that process by attacking this receptor impedes differentiation and also compromises the early down regulation of RB tumor suppressor gene expression which normally precedes differentiation. These findings provide additional support for a potential role for down regulating RB expression in promoting cell differentiation, and suggest the possibility that RB may be either a target or intermediate mediator of CSF-1 actions.
Antibodies, Monoclonal↗
Expression of the c-fms proto-oncogene during human monocytic differentiation.
The McDonough strain of the feline sarcoma virus contains a transforming gene (v-fms) which contains partial nucleotide homology with proto-oncogenes encoding tyrosine kinases. One of the v-fms-encoded products, gp140fms, is a cell surface transmembrane glycoprotein that may function as a growth factor receptor. Although c-fms transcripts have been detected in placental trophoblasts and normal human bone marrow, the role of the c-fms gene product is unknown. We now report that induction of monocytic, but not granulocytic, differentiation of human HL-60 leukaemic cells is associated with expression of c-fms, preceded by that of c-myc and c-fos. Because c-fms transcripts are also detectable in peripheral blood monocytes and in blasts from certain patients with myelomonocytic leukaemia, the c-fms gene product may play a role in monocytic differentiation.
Acetamides↗