Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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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.
Leuk Lymphoma 1994 Sep
PMID: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. 785 91

Translocations involving chromosome band 11q23 are associated with acute lymphocytic and myelomonocytic leukemias with poor clinical prognosis. Pulsed-field gel electrophoresis (PFGE) was used to characterize the breakpoint region that has been mapped within a 300-kb fragment between the genes CD3G and PBGD. Using CD3G as a marker on SfuI-restricted DNA separated by PFGE, we detected a rearrangement involving 11q23 in the cell line B1 with a t(4;11) and in the leukemic cells of two patients, one with a t(2;11) and one with a t(11;19). In comparison, lymphoblastoid cell lines established from normal peripheral blood lymphocytes of these two patients had a normal karyotype and showed germline configuration, thus excluding RFL polymorphisms. Digestion of DNA with BssHII or SalI showed heterogeneity of 11q23 involving breakpoints. A rearrangement in the t(4;11) containing lymphoma cell line Karpas422 was seen only with the chromosome 4 probe KIT on SalI-digested DNA. PFGE is a reliable method for the mapping and detection of complex breakpoint regions. The breakpoints on 11q23 involve different introns of the highly spliced HRX/ALL-1/MLL gene.
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PMID:Detection of chromosome 11q23 involving translocations by pulsed field gel electrophoresis. 816 79

The FLT3 gene encodes a protein that appears to function as a receptor for a hematopoietic growth factor; together with the KIT and FMS receptors, FLT3 belongs to the superfamily of receptors with tyrosine kinase activity. We examined the expression of FLT3 mRNA in 36 human leukemia-lymphoma cell lines using Northern blot analysis. FLT3 transcripts were found in seven of seven pre B-ALL cell lines (derived from cases with pre B-acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast crisis), and in one of six B-cell lines (namely in a cell line established from a hairy cell leukemia). FLT3 message was not detected in five T-cell, five myeloid, four monocytic, four erythroid and five megakaryocytic cell lines. Two major mRNA species were expressed differentially by positive cell lines. KIT mRNA expression was also investigated in the same panel of cell lines, but was found only in cell lines with erythroid and megakaryocytic features (and not in any of the FLT3-positive cell lines). The pattern of expression of FLT3 contrasts with the transcription of FMS and KIT and suggests that the FLT3 product may play a role primary in immature lymphoid cells.
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PMID:Expression of the FLT3 gene in human leukemia-lymphoma cell lines. 818 45

The (2;5)(p23;q35) translocation which results in the fusion of the NPM (nucleophosmin) gene on chromosome 5q35 with the novel ALK (anaplastic lymphoma kinase) gene on chromosome 2p23 [S.W. Morris et al., Science (Washington DC), 263: 1281-1284, 1994] is associated with Ki-1 (CD30)-positive anaplastic large cell lymphomas (ALCL); a group of morphologically and immunophenotypically heterogenous high grade large cell lymphomas (LCL), which share many characteristics with Hodgkin's disease (HD), including the presence of variable numbers of Reed-Sternberg-like cells and the expression of CD30 antigen. Using a DNA probe immediately 5' to the NPM coding sequences, we have examined NPM gene rearrangements by Southern blotting in 5 Ki-1-positive lymphoma cell lines carrying a translocation involving the 5q35 breakpoint and in 25 Ki-positive lymphoma tumors, including 9 HD. Using this method, we detected rearrangements in all cell lines with apparent clustering of the breakpoints. Analysis of 25 Ki-1-positive lymphomas indicated that only 4 neoplasms, including two HD, had NPM gene rearrangements. Thus, our findings suggest that only a subset of ALCL has detectable involvement of the NPM gene. In addition, the presence of NPM gene rearrangements in HD indicates the involvement of this gene in a fraction of HD. Thus, NPM gene rearrangements may identify a certain subtype in ALCL and HD which may be closely related.
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PMID:Nucleophosmin (NPM) gene rearrangements in Ki-1-positive lymphomas. 818 71

The incidence of genetic abnormalities have been investigated in a variety of preleukaemic states RAS and FMS oncogene, p53 suppressor gene mutations and monoclonality in myelodysplastic syndromes (MDS), a paradigm for pre-leukemias have been observed. Other patients at risk of developing either secondary leukaemia or evolving into leukaemia have been similarly studied including haematologically normal patients in remission from lymphoma. Time from treatment to detection of genetic abnormalities is a significant factor in some of these patients which is consistent with the expansion of an abnormal clone. A case of non-dysplastic MDS has been identified with a 7q-karyotypic abnormality typical of therapy related MDS, abnormal progenitor growth and RAS mutations but with normal clinical features. Normal individuals have also been under investigation and found to have a low incidence of proto-oncogene mutations. A prospective study should enable us to determine if these parameters are indeed prognostic indicators.
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PMID:Genetic lesions in preleukemia. 824 36

The proto-oncogene c-met encodes a heterodimeric (alpha, beta) tyrosine kinase receptor which binds the hepatocyte growth factor (HGF). Recently, overexpression of the Met/HGF receptor gene has been detected in fresh samples of carcinomas and in epithelial tumor cell lines but not in cell lines derived from human leukemia and lymphoma. Our analysis of 50 primary samples of human leukemia and lymphoma and 23 hematopoietic cell lines revealed expression of mRNA and protein of the met/HGF receptor in 6 out of the 73 hematopoietic tumor samples analyzed. Four of the six samples positive for expression of the Met/HGF receptor gene were derived from patients with Hodgkin's disease. In addition, in one Burkitt's lymphoma cell line and in one acute myeloid leukemia (AML), expression of the Met/HGF receptor gene was detected. In normal unstimulated lymphocytes, granulocytes or monocytes we did not find expression of the Met/HGF receptor gene. Upon stimulation with the phorbol ester TPA we detected a weak expression of Met/HGF receptor specific transcripts of 9.0 kb in peripheral blood mononuclear cells of a healthy donor. Cytogenetic analyses of three of the four cell lines which express the Met/HGF receptor gene revealed structural or numerical abnormalities of the long arm of chromosome 7, where the Met/HGFR gene is located, in each of the three cell lines analyzed. In one of these cell lines (L540) the Met/HGFR gene is translocated to a marker chromosome. Southern blot and pulsed field gel electrophoresis experiments did not show any rearrangement in a region of 600 kb around the Met/HGF receptor gene excluding an activation of Met/HGFR by a TPR/Met oncogenic rearrangement as described for MNNG-HOS cells and for some gastric tumors. Our data indicate that the Met/HGFR gene is deregulated in a few cases of human leukemia, Burkitt's lymphoma and Hodgkin's disease possibly by chromosomal rearrangements resulting in an overexpression of the normal Met/HGF receptor mRNA and protein without formation of a hybrid gene.
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PMID:The Met/hepatocyte growth factor receptor (HGFR) gene is overexpressed in some cases of human leukemia and lymphoma. 828 71

HTLV-I, II and HIV-1, 2 are T-cell tropic viruses, all belonging to the retrovirus family. These viruses are transmitted horizontally by intimate contact or through blood products. The study of chromosomal changes in these T cells may enhance our understanding of the nature and mechanism of these viral infections. However, because of the cytopathic effect of these viruses on T cells, the direct observation of abnormalities in these cells is sometimes difficult. We performed chromosomal analysis on six HTLV-I cell lines from patients with HTLV-I-positive leukemia/lymphoma, one HTLV-I variant cell line, and two HTLV-II-positive cell lines. The results of these studies were compared with the findings in an earlier (published) study of direct preparations and short-term cultures of cells from 11 HTLV-I-positive NIH patients. Our study also included cytogenetic analysis of seven established cell lines and six normal peripheral bloods infected in vitro with the HTLV-IIIB strain of HIV-1 (five cell lines and six bloods) or HIV-2 (two lines); all were studied both before and after viral infection. The results showed that all six HTLV-I cell lines and the variant cell line had multiple chromosomal changes: three lines had deletions of chromosome 6, with breakpoints between q21 and q25. Nine of the 11 NIH patients with HTLV-I had clonal abnormalities, and six of these nine had chromosome 6 deletions with breakpoints ranging from band q11 to band q23. The high incidence of 6q involvement may be of considerable significance in this clinical subgroup of HTLV-I patients. The two HTLV-II cell lines were established from patients suffering from HTLV-II infection. Both of these cell lines had translocations of chromosome 21 at p11, and both had extra copies of chromosome 20; no known oncogenes or receptors are located on these two chromosomes. Chromosome 17 was the chromosome most frequently involved (three lines) in the five HIV-1-infected cell lines, followed by chromosomes 3 and 21; it is of interest that NGL (also known as C-ERBB2 or NEU oncogene), CD7 (a lymphocyte antigen), HTLV-1 receptor, NGFR (nerve growth factor receptor), and MIC6 are all cell surface antigens coded by genes on chromosome 17q. No specific chromosome abnormalities were found in the normal blood samples infected with HIV-1, and no unique chromosome changes were noted in the two cell lines infected with HIV-2; however, the infected H9 line had a chromosome 17 abnormality, a translocation involving band 17p11.
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PMID:Chromosome studies in HTLV-I, -II, and HIV-1, -2 cell lines infected in vivo and in vitro. 831 77

The FMS proto-oncogene encodes for the colony-stimulating factor 1 receptor (CSF-1R), whose expression within the haematopoietic system has previously been thought to be restricted to cells of the mononuclear phagocyte lineage. We have studied the expression of the CSF-1R in peripheral blood mononuclear cells by indirect immunofluorescence and flow cytometry. FMS expression was detected on both monocytes and B lymphocytes from all samples analysed, including 14 haematologically normal individuals and 31 patients (23 in remission following cytotoxic therapy for lymphoma, six with B-cell chronic lymphocytic leukaemia and two with chronic myelomonocytic leukaemia). The level of FMS expression on B lymphocytes was lower than the level of expression detected on monocytes isolated from the same sample. FMS mRNA expression in B lymphocytes has been confirmed by a reverse transcription-polymerase chain reaction (RT-PCR)-based technique and Northern blot analysis. Thus, FMS may play a role in the normal function of B lymphocytes and, because of its potential oncogenic activity, may contribute to the pathogenesis of malignancies of this cell type.
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PMID:Expression of the colony-stimulating factor 1 receptor in B lymphocytes. 842 43

Using the polymerase chain reaction with degenerate oligonucleotides derived from conserved motifs within the catalytic kinase domain of protein tyrosine kinases, and RNA extracted from embryonic stem cells, sequences that encode a segment of the kinase domain of several potentially novel receptor tyrosine kinases (RTKs) have been identified. One of these was selected for further study because in Northern analysis it hybridized to RNA from multipotential hematopoietic cell lines, but not from lines representative of lineage-committed cells. A cDNA for this receptor, designated developmental tyrosine kinase (DTK), was isolated and encodes a protein with structural similarities to AXL. Together these receptors form a new class of RTK. DTK is expressed in a number of human leukemic cell lines, and in the blasts of 6 of 11 patients with acute myeloid leukemia (AML) analyzed. The structure of DTK suggests that it may function as a cell adhesion molecule, and mediate cell-to-cell or cell-matrix interactions between hematopoietic cells and their respective microenvironments.
Leuk Lymphoma 1995 Aug
PMID:Identification of a novel receptor tyrosine kinase expressed in acute myeloid leukemic blasts. 852 51

Fifty-six cases of anaplastic large cell lymphoma (ALCL), 23 cases of Hodgkin's disease, and 16 cases of diffuse large cell lymphoma were investigated for the t(2;5)(p23;q35) translocation. The translocation was detected by using cytogenetic analysis, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry with P80 antibody directed against the kinase domain of anaplastic lymphoma kinase (ALK) of the chimeric NPM/ALK protein. In all but three cases of ALCL, we found an agreement between cytogenetic analysis, RT-PCR, and P80 staining. However, in one case, the t(2;5) translocation was detected with cytogenetic analysis, but RT-PCR and P80 staining were found to be negative. Conversely, in another case the karyotype was normal, but the hybrid mRNA and P80 staining were found to be positive. In one case, malignant cells showed a translocation involving chromosomes 1q25 and 2p23 and were strongly positive for P80 staining. Such a result could be expected because P80 antibody detects the kinase domaine of the ALK protein encoded by chromosome 2p23. Overall 73.2% (41 of 56) of cases were found to be positive. However, the highest percentage (23 of 26 cases; 88.5%) of P80 positive cases was found in children compared with 60% (18 of 30 cases) in adult ALCL (P < .05). In Hodgkin's disease, Reed-Sternberg cells were found to be clearly negative by RT-PCR and with P80 antibody. The latter results suggest that Hodgkin's disease and t(2;5)-positive ALCL are distinct biological entities and that the demonstration of the t(2;5) translocation is of diagnostic importance in differentiating these two entities. The results of the present study indicate that immunohistochemistry with P80 antibody is a reliable method for detecting NPM/ALK chimeric protein.
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PMID:High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. 854 53


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