Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A molecular probe was prepared with specificity for the human cellular homologue of transforming sequences represented within the McDonough strain of feline sarcoma virus (v-fms). By analysis of a series of mouse-human somatic cell hybrids containing variable complements of human chromosomes it was possible to assign this human oncogene, designated c-fms, to chromosome 5. Regional localization of c-fms to band q34 on chromosome 5 was accomplished by analysis of Chinese hamster-human cell hybrids containing as their only human components, terminal and interstitial deleted forms of chromosome 5. The localization of c-fms to chromosome 5 (q34) is of interest in view of reports of a specific, apparently interstitial, deletion involving approximately two thirds of the q arm of chromosome 5 in acute myelogenous leukemia cells.
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PMID:Chromosomal localization of the human c-fms oncogene. 668 66

Granulocyte colony-stimulating factor (G-CSF) can elicit responses that include proliferation, granulocytic differentiation, and activation of cellular functions in target cells. The biochemical pathways responsible for transduction of these signals from the G-CSF receptor (G-CSFR) have not been defined. In this report, we show that, in murine (NFS-60) and human (OCI-AML 1) myeloid leukemia cell lines and in murine pro-B-lymphocytic cells, BAF/B03, transfected with the murine G-CSFR, proliferative responses to G-CSF are associated with rapid activation of p42 and p44 MAP kinases and p21ras. Truncation of the cytoplasmic portion of the murine G-CSFR at residue 646 but not at residue 739 abolished G-CSF-induced stimulation of cellular proliferation as well as activation of MAP kinase and p21ras in transfected BAF/B03 cells. G-CSF-induced granulocytic differentiation of the murine leukemic cell line 32DC13(G) occurred in the absence of detectable activation of p42 MAP kinase. Nonproliferative responses to G-CSF in the human promyelocytic cell line HL-60 and in human neutrophils were similarly associated with no MAP kinase activation. These results imply that differing cellular effects of G-CSF may be involve the recruitment of differing signal transduction pathways with the p21ras/MAP kinase pathway being limited to proliferative responses.
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PMID:Proliferative but not nonproliferative responses to granulocyte colony-stimulating factor are associated with rapid activation of the p21ras/MAP kinase signalling pathway. 750 13

Mutations of signal transducing molecules such as Ras have been shown to confer a growth advantage in leukaemic blasts and contribute to the pathogenesis of the disease. Alterations of signal transducing molecules other than Ras may play a role in leukaemogenesis. Knowledge of such mutations could also further our understanding of the normal signalling processes. We have therefore studied the coding sequence of the GM-CSF receptor alpha chain (GM-CSFR alpha) in patients with acute myeloid leukaemia (AML) and non-AML controls using single strand conformation polymorphism (SSCP) analysis. Abnormalities were detected in 4/32 AML patients (13%) and 2/15 non-AML controls (13%). Direct sequencing of PCR products revealed five different base substitutions. Three were conservative, two caused amino acid changes. The base substitution leading to amino acid change alanine to glycine at position 17 was found in both an AML patient and a control. It lies in the signal sequence and does not affect the mature protein. The other base change altering arginine to glutamine at position 164 is unlikely to influence the receptor structure as this structural position in the chain is not well conserved in members of the cytokine receptor family. Both amino acid changes were constitutive alterations as they could be demonstrated in the patients' children. The base changes described in the AML patients thus represent polymorphisms and do not contribute to the pathogenesis of AML.
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PMID:Analysis of mutations in the GM-CSF receptor alpha coding sequence in patients with acute myeloid leukaemia and haematologically normal individuals by RT-PCR-SSCP. 752 90

Point mutations at codons 301 and 969 of the FMS proto-oncogene have been reported in both myelodysplasia (MDS) and acute myeloid leukaemia (AML). We report here the incidence of such mutations in patients at risk of developing secondary MDS and AML. Peripheral blood DNA from 70 patients in remission from lymphoma was screened for mutations by oligonucleotide (ONH) using mutant specific probes. Codon 969 mutations were detected in 11 of the 70 (15.7%) cases. No codon 301 mutations were detected. Five of these mutations were confirmed using an independent technique (single nucleotide primer extension analysis, SNPE) and a further mutation was detected in a single patient using single-stranded conformational polymorphism analysis (SSCP). No codon 969 mutations were detected in 62 lymphoma biopsy specimens from these patients or from three patients with detectable FMS mutations where pre-therapy marrow was investigated by ONH. No mutations at either codons 301 or 969 were detected by ONH in 61 normal controls. Somatic mutations at codon 969 of the FMS gene occur commonly following cytotoxic therapy for lymphoma and their detection indicates the presence of a clonally expanded population of abnormal cells.
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PMID:FMS mutations in patients following cytotoxic therapy for lymphoma. 776 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.
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PMID:RAS and FMS mutations following cytotoxic therapy for childhood acute lymphoblastic leukaemia. 756 28

Acute myelogenous leukemia (AML) cells express CD23 surface antigen after in vitro treatment with various cytokines, including interleukin-4 (IL-4) and interferon gamma. Subsequent ligation of CD23 by specific monoclonal antibody (MoAb) induces substantial morphologic and functional modifications in these cells. In the present study, we investigated the role of CD23 in the proliferation and the maturation of leukemic cells from AML patients or the U937 cell line. CD23+ cell treatment with CD23 MoAb inhibited the proliferation of leukemic cells. This correlated with their terminal differentiation after 7 to 9 days incubation because they (1) definitively lost their growth capacity; (2) adhered to culture flasks and became monocyte/macrophage-like; and (3) expressed mature monocyte markers including nonspecific esterases. Intracellular mechanism of this antitumoral effect was then analyzed in U937 cells. Induction of high-density surface CD23 expression by IL-4 or granulocyte-macrophage colony-stimulating factor coincided with a transient decrease of U937 cell proliferation. CD23 ligation during this low-proliferative phase induced a rapid activation of L-arginine-dependent pathway and the intracellular accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). Induction of these early messengers was followed by the activation of nuclear factor-kB transcription factor and the modulation of proto-oncogene expression by U937 cells. Whereas U937 cell treatment with IL-4 decreased c-fos/c-jun expression, CD23 MoAb reinduced c-fos/c-jun and promoted the expression of cell maturation-associated proto-oncogenes junB and c-fms, during the first 24 hours. Both IL-4 and CD23 MoAb downregulated the expression of c-myb. CD23 ligation also induced the production of TNF alpha by U937 cells. Inhibitors of cAMP and nitric oxide reversed CD23-mediated modification in U937 cells. These data evidence the ability of CD23 surface antigen to mediate terminal differentiation of early leukemic myelomonocytic cells.
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PMID:Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. 794 82

The proto-oncogenes c-fms and c-kit belong to a family of growth factor receptors possessing protein kinase activity. It has been shown that transfection of a c-fms gene carrying a point mutation at codon 301, leads to a ligand-independent transformation of mouse NIH3T3 cells. In human acute myeloid leukemia (AML), point mutations at codon 301 of the c-fms gene have been observed implying an important role in the transformation process. The possibility of a point mutation of the c-kit proto-oncogene was investigated. We sequenced a segment of the c-kit proto-oncogene coding for a part of the extracellular domain. This segment was 40.7% homologous to the c-fms region encompassing codon 301. c-DNA was prepared from peripheral blood or bone marrow cells from 25 patients with AML, from four patients with myelodysplastic syndrome (MDS) and from three human myeloid cell lines. The region of interest was amplified with two rounds of polymerase chain reactions (PCR) with nested primers and directly sequenced. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the c-kit gene do not seem to play an important role in the transformation process of human acute leukemia.
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PMID:Absence of point mutations in a functionally important part of the extracellular domain of the c-kit proto-oncogene in a series of patients with acute myeloid leukemia (AML). 812 54

Point mutations in codons 12, 13, and 61 of N-ras have consistently been reported in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) using a variety of techniques. Recently mutations in codons 301 and 969 of c-fms, preferentially involving TAT-to-TGT at codon 969, have also been identified in these disorders by allele specific oligonucleotide (ASO) hybridization. We have developed allele specific restriction analysis (ASRA) protocols for the detection of point mutations in the critical codons of these genes. ASRA involves enzymatic digestion of polymerase chain reaction (PCR)-induced restriction sites which are specific for normal but not mutant alleles. A total of 11 N-ras mutations were observed in 10 out of 46 AML patients, consistent with the reported frequency of N-ras mutations when alternative techniques of comparable sensitivity are used. In contrast, c-fms point mutations were not detected in a similar number of patients with AML, including 39 studied for mutations in both N-ras and c-fms, and this difference is statistically significant (p < 0.003). A more sensitive technique (ASRA + ASO hybridization) also failed to detect TAT-to-TGT substitutions at codon 969 in a subgroup of M4-AML patients considered to be at greatest risk of harboring c-fms mutations. This study suggests that c-fms mutations at codons 301 and 969 are not important in the pathogenesis of AML in the vast majority of patients.
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PMID:c-fms point mutations in acute myeloid leukemia: fact or fiction? 832 Oct 48

Similar to two other hematopoietic growth factor receptors, the c-fms (macrophage colony-stimulating factor receptor) and the c-kit genes, c-mpl has been discovered through the study of oncogenic retroviruses. Unlike c-fms and c-kit, which both belong to a subgroup of tyrosine kinase receptors, the c-mpl proto-oncogene encodes a new member of the cytokine receptor superfamily. We have studied the expression of c-mpl in a series of 105 patients with hematologic malignancies using Northern blot analysis. The levels of c-mpl transcripts in lymphoid malignancies and in chronic myeloproliferative disorders were not significantly different from those found in normal bone marrow cells, in which c-mpl was barely detectable. In contrast, c-mpl expression was increased in 26 of 51 patients with acute myeloblastic leukemia (AML) and in 5 of 16 patients with myelodysplastic syndromes. Amplification of the c-mpl gene was detected in genomic DNA of one M4 AML patient. There was no significant correlation between c-mpl expression and the French-American-British classification of AML. Patients with high c-mpl expression appeared to belong to a subgroup of AML with a low rate of complete remission and a poor prognosis, including secondary leukemia and AML with unfavorable cytogenetic abnormalities.
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PMID:Expression of the c-mpl proto-oncogene in human hematologic malignancies. 839 55

Acute myeloid leukemia blasts express dual affinity (high and low) granulocyte-macrophage colony-stimulating factor (GM-CSF) binding, and the high affinity GM-CSF binding is counteracted by excess interleukin-3 (IL-3). Neutrophils express a single class of GM-CSF-R with intermediate affinity that lack IL-3 cross-reactivity. Here we demonstrate the differentiation associated changes of GM-CSF binding characteristics in three models representative of different stages of myeloid maturation. We find that high affinity GM-CSF binding is converted into intermediate affinity binding, which still cross-reacts with IL-3, beyond the stage of promyelocytes. During terminal maturation towards neutrophils, IL-3 cross-reactivity is gradually lost. We sought to determine the mechanism underlying the affinity conversion of the GM-CSF-R. Northern and reverse transcriptase-polymerase chain reaction analysis of GM-CSF-R alpha and -beta c (KH97) transcripts did not provide indications for the involvement of GM-CSF-R splice variants in the formation of the intermediate affinity GM-CSFR complex. In COS-cell transfectants with increasing amounts of beta c in the presence of a fixed number of GM-CSF-R alpha chains, the high affinity GM-CSF binding converted into intermediate affinity GM-CSF binding. These results are discussed in view of the concept that increasing expression of beta c subunits may cause alternative oligomerization of the GM-CSF-R alpha and -beta c subunits resulting in the formation of intermediate rather than high affinity GM-CSFR alpha.beta c complexes.
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PMID:Granulocyte-macrophage colony-stimulating factor receptors alter their binding characteristics during myeloid maturation through up-regulation of the affinity converting beta subunit (KH97). 848 85


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