Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.
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PMID:Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. 912 81

Nucleobindin (Nuc) was originally found to be an enhancement factor of anti-DNA antibody production secreted by a lymphoid cell line derived from a lymphoproliferative MRL/lpr mouse. It has been shown that Nuc has a unique structure containing a DNA- and two calcium-binding domains, and a leucine zipper motif, but its biological roles have not yet been fully elucidated. Expression of Nuc was first studied in human lymphocytes. Expression of Nuc mRNA in normal peripheral blood mononuclear cells was significantly increased upon mitogen stimulation. Anti-human Nuc monoclonal antibody H-1D8 immunoprecipitated Nuc protein in the nuclear extract of Molt-4 cells. Furthermore, in the immunohistochemical staining of tumor specimens from 108 patients with non-Hodgkin's lymphoma (NHL) with H-1D8, H-1D8-positive cells were observed in nearly all cases in varying frequency. According to the Working Formulation, the percentage of cases in which more than 90% of the tumor cells were stained with H-1D8 was 65% in the high grade of the histological malignancy, 54% in the intermediate grade, and 22% in the low grade; however, normal cells surrounding the tumor cells were virtually negative for H-1D8. These results showed that the level of Nuc expression in human lymphocytes reflects the status of activation or proliferation of the cells, thus providing a clue for the further investigation into biological roles of Nuc. In addition, it might be applicable to the clinicopathological estimation of NHL as a novel indicator.
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PMID:Upregulation of nucleobindin expression in human-activated lymphocytes and non-Hodgkin's lymphoma. 958 60

Expression of BCR/ABL, a constitutively active tyrosine kinase, is a primary event in the pathogenesis of chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph+ALL). Inhibition of the BCR/ABL kinase activity in the BV173 CML cell line with STI571 resulted in a significant overexpression of a 10-kb novel mRNA, found to be the human ortholog of the murine Bach2, a B-cell-specific transcription factor. The human BACH2 cDNA is >9,120 bp long and includes an open reading frame of 2,526 bp encoding a protein with a basic leucine zipper (bZip) and a BTB/POZ domain, mediating DNA-binding and heterodimerization. BACH2 was consistently upregulated (2-10-fold) in all 10 Ph+ lymphoid lines tested following BCR/ABL inhibition. In CML myeloid cell lines (n = 8) and BCR/ABL-negative lines (n = 6), BACH2 was either undetectable by Northern blotting or did not change in response to STI571, suggesting that BACH2 repression by BCR/ABL may be specifically relevant to lymphoid transformation. Quantitative RT/PCR revealed a significantly lower level of BACH2 expression in leukocytes from patients with CML (n = 24) as compared to normal individuals (n = 23) (P < 0.0005). Moreover, CD34+ cells treated in vitro with STI571 exhibited a consistent upregulation of BACH2 in 8 of 10 CMLs but in none of the 9 normal individuals tested. Transcription regulation of BACH2 in BCR/ABL-positive cells was exerted via the MEK pathways, as shown by their responses to the U0126-specific inhibitor. Radiation hybrid mapping and FISH revealed that BACH2 is located on chromosome 6, band q15, a region frequently associated with deletions in ALL and non-Hodgkin's lymphoma, suggesting its possible role as a tumor suppressor gene. However, no rearrangement or loss of signal was observed by Southern blotting in 34 lymphomas, 10 B-cell ALLs, or seven reactive lymph nodes. The pattern of BACH2 expression in BCR/ABL-positive cells suggests that transcriptional repression by this regulator is impaired in CML and may contribute to the emergence of lymphoid blast crisis.
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PMID:Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene. 1174 76

The transcription factor CCAAT/enhancer binding protein (C/EBP)alpha is a myeloid-specific transcription factor which is required for normal myeloid differentiation. C/EBPalpha is encoded by an intronless gene that is 2783 bp long and maps to human chromosome 19q13.1. C/EBPalpha is a member of the basic region leucine zipper (bZIP) class of DNA-binding proteins. The loss of function of C/EBPalpha has leukemogenic potential. Four types of polymorphisms and 25 mutations (3 already known mutations and 22 novel mutations) were detected in CEBPA (gene for the transcription factor CCAAT/enhancer binding protein (C/EBP) alpha) in analysed samples from 390 patients with myelodysplastic syndrome (MDS) and hematologic malignancies. CEBPA mutations were found in 14/152 (9.2%) of acute myeloid leukemia (AML) patients' samples, 6/143 (4.2%) of MDS patients' samples, 2/56 (3.6%) of non-Hodgkin's lymphoma (NHL) patients' samples and 2/39 (5.1%) of multiple myeloma (MM) patients' samples. No C/EBPalpha mutations were detected in healthy donors (41 individuals). We discuss how these mutations can affect the cellular function of C/EBPalpha and block the myeloid differentiation.
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PMID:CEBPA polymorphisms and mutations in patients with acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and non-Hodgkin's lymphoma. 1818 75

C/EBPalpha (CCAAT/enhancer binding protein alpha) belongs to the family of leucine zipper transcription factors and is necessary for transcriptional control of granulocyte, adipocyte and hepatocyte differentiation, glucose metabolism and lung development. C/EBPalpha is encoded by an intronless gene. CEBPA mutations cause a myeloid differentiation block and were detected in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma and non-Hodgkin's lymphoma (NHL) patients. In this study we identified in 41 individuals from 824 screened individuals (290 AML patients, 382 MDS patients, 56 NHL patients and 96 healthy individuals) a single class of 23 deletions in CEBPA gene which involved a direct repeat of at least 2 bp. These mutations are characterised by the loss of one of two same repeats at the ends of deleted sequence. Three most frequent repeats included in these deletions in CEBPA gene are CGCGAG (493-498_865-870), GCCAAGCAGC (508-517_907-916) and GG (486-487_885-886), all according to GenBank accession no. NM_004364.2. A mechanism for deletion formation between two repetitive sequences can be recombination events in the repair process. Double-stranded cut in DNA can initiate these recombination events of adjacent DNA sequences.
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PMID:Nature of frequent deletions in CEBPA. 1965 29