UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
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The type I human T-cell leukemia virus (HTLV-I) encodes a 40-kD nuclear trans-regulatory protein termed Tax that transcriptionally activates the HTLV-I long terminal repeat (LTR), as well as select [corrected] cellular and heterologous viral promoters. Tax does not bind DNA specifically but, rather, acts in a more indirect manner. Tax activation of the HTLV-I LTR is mediated through constitutively expressed cellular factors that bind to cAMP response elements (CREs) present within the 21-bp enhancers of the LTR. In contrast, Tax transactivation of the interleukin-2 receptor-alpha gene (IL-2R alpha) and LTR of the type 1 human immunodeficiency virus (HIV-1) involves the induced nuclear expression of NF-kappa B. We now report the identification of missense mutations within the tax gene that functionally segregate these two pathways of trans-activation. Additionally, we demonstrate that the carboxyl terminus of the Tax protein, despite its acidic and predicted alpha-helical structure, is completely dispensable for trans-activation through either of these transcription factor pathways. Finally, we demonstrate that mutations within a putative zinc finger domain disrupt the nuclear localization of Tax and abolish trans-activation. These results demonstrate that Tax trans-activation of viral and cellular promoters involves at least two mechanisms of host transcription factor activation and suggest that this activation is likely mediated through distinct functional domains.
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PMID:Identification of HTLV-I tax trans-activator mutants exhibiting novel transcriptional phenotypes. 227 22

Cytogeneticists recognize that karyotypic abnormalities are associated with specific malignancies. In 1960, Nowell described the Philadelphia chromosome (Ph) and its relationship to chronic myelogenous leukemia (CML). Subsequent work in molecular genetics and biology has revealed that the Ph is a translocation that causes fusion of gene sites that code for the break cluster region (BCR) and the avian blastic leukemia (ABL) proteins. This so-called fusion protein is present in a large percentage of the patients who have CML. A related fusion protein is seen in about one third of patients with acute lymphoblastic leukemia. The BCR-ABL fusion protein results in increased tyrosine kinase activity. The mechanism of action is thought to be via signal transduction related to guanosine triphosphatase activating protein which interacts with a ras-p21 binding protein. Acute promyelocytic leukemia (APL) is associated with the cytogenetic abnormality of t(15;17). This alters the promyelocytic leukemia (PML) and the retinoic acid receptor alpha (RARA) gene sites. Two fusion proteins are the result of this cytogenetic abnormality. They are termed PML-RARA and RARA-PML. Only one, the PML-RARA, is associated with APL. The PML-RARA chimeric protein has two zinc finger-like regions. It retains the ligand binding domain of RARA. The protein called PML has some similarities with a family of proteins which are thought to fuse to proto-oncogenes and to act as transforming proteins. The role of classical cytogenetics and the added capability of molecular biology has helped to elucidate some of the potential mechanisms for the development of cancer and provided additional understanding of neoplasia. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytogenetics, gene fusions, and cancer. 748 13

Variants of the t(15;17)(q22;q12-q21) chromosomal rearrangement associated with acute promyelocytic leukemia (APL) have been previously described and they frequently involve either chromosome 15 and/or 17. Previously we reported a rare variant t(11;17). We now describe two patients with myelodysplastic syndrome (MDS) that transformed to APL-like leukemia. Both had trisomy 11 at the diagnosis of APL-like leukemia. Following treatment for APL, patient 1 reverted to MDS and showed a normal karyotype. When leukemia recurred, his bone marrow karyotype was 47,XY,t(4;11), +11,der(22)t(1;22). Both patients were treated with all-trans retinoic acid (ATRA) for APL for 5 weeks, but failed to respond. The karyotype of patient 1 after ATRA treatment was 46,XY,t(4;11); the trisomy 11 had been lost and the bone marrow was replaced with immature myeloblasts without promyelocytes. In patient 2, the karyotype remained the same as at diagnosis, i.e., 47,X,-Y,dir ins(4;7),del(5), +6,del(7), +8, + 11,-18. Molecular analysis by reverse transcriptase PCR analysis showed the presence of wild type retinoic acid receptor alpha (RARA) and the absence of the PML-RARA chimeric gene associated with t(15;17). Additional analysis of PLZF, a new zinc finger gene associated with t(11;17), also showed the absence of this hybrid gene. These data support the concept that APL is a heterogeneous disorder and that variants with chromosome 11 rearrangement exist that do not respond to ATRA.
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PMID:Myelodysplastic syndrome transforming to acute promyelocytic-like leukemia with trisomy and rearrangement of chromosome 11. 751 69

We have identified and further characterized a Caenorhabditis elegans gene, CEZF, that encodes a protein with substantial homology to the zinc finger and leucine zipper motifs of the human gene products AF10, MLLT6, and BR140. The first part of the zinc finger region of CEZF has strong similarity to the corresponding regions of AF10 (66%) and MLLT6 (64%) at the cDNA level. As this region is structurally different from previously described zinc finger motifs, sequence homology searches were done. Twenty-five other proteins with a similar motif were identified. Because the functional domain of this motif is potentially disrupted in leukemia-associated chromosomal translocations, we propose the name of leukemia-associated protein (LAP) finger. On the basis of these comparisons, the LAP domain consensus sequence is Cys1-Xaa1-2-Cys2-Xaa9-21-Cys3-Xaa2-4 -Cys4-Xaa4-5-His5-Xaa2-Cys6-Xaa12-46 - Cys7-Xaa2-Cys8, where subscripted numbers represent the number of amino acid residues. We review the evidence that this motif binds zinc, is the important DNA-binding domain in this group of regulatory proteins, and may be involved in leukemogenesis.
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PMID:The leukemia-associated-protein (LAP) domain, a cysteine-rich motif, is present in a wide range of proteins, including MLL, AF10, and MLLT6 proteins. 756 8

Promyelocyte Leukemia Zinc Finger (PLZF) is a Kruppel-like zinc finger gene previously identified in a unique case of acute promyelocytic leukemia (APL) as the counterpart of a reciprocal chromosomal translocation involving the retinoic acid receptor alpha gene (RAR alpha). PLZF is highly conserved throughout evolution from yeast to mammals. To elucidate its role, we isolated the murine PLZF gene and studied its expression during embryogenesis. PLZF is expressed in an extremely dynamic pattern with transcripts appearing at E 7.5 in the anterior neuroepithelium and quickly spreading to the entire neuroectoderm until E 10. At E 8.5, PLZF is transcribed in most of the endoderm. During mid to late gestation PLZF is expressed in restricted domains of the developing CNS as well as in specific organs and body structures. We have focused our attention on the developing forebrain where PLZF is transcribed in a transverse, segment-like domain corresponding to the anterior pretectum, in the alarmost part of the dorsal thalamus, in the epithalamus, and in the hypothalamus along a defined longitudinal subdomain. Furthermore, PLZF is expressed in several segmentary boundaries, among them, the zona limitans intrathalamica. Combined analysis with other regionally restricted genes, such as Orthopedia and Dlx1, indicates that in the hypothalamus the PLZF domain is contained within that of Orthopedia and both are complementary to that of Dlx1. Our data suggest a role for PLZF in the establishment and maintenance of transverse identities, longitudinal subdomains, and interneuromeric boundaries, providing additional evidences in favor of the neuromeric organization of the forebrain.
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PMID:Developmental analysis of murine Promyelocyte Leukemia Zinc Finger (PLZF) gene expression: implications for the neuromeric model of the forebrain organization. 762 23

We have analyzed the roles of Gag protein nucleocapsid (NC) domains in the packaging or encapsidation of retroviral RNAs into virus particles. We found that mutation of both zinc finger motifs of the human immunodeficiency virus (HIV) NC domain reduced but did not eliminate encapsidation of the HIV viral RNA. However, the NC mutations also resulted in a three- to fourfold reduction in the specificity of RNA encapsidation, as determined by comparison of virus-associated genomic and spliced RNA levels. As a complementary approach, we replaced the NC domain of Moloney murine leukemia virus (M-MuLV) with that of HIV. Chimeric virus particles assembled efficiently, were of wild-type M-MuLV density, and cross-linked at NC cysteines. In encapsidation studies, wild-type M-MuLV precursor Gag (PrGag) proteins packaged M-MuLV transcripts more efficiently than HIV RNAs. In contrast, chimeric PrGag proteins possessing the HIV-1 NC domain in the context of the M-MuLV MA (matrix), p12, and CA (capsid) domains encapsidated HIV transcripts to a greater extent than M-MuLV transcripts. Our results support the notion that retroviral NC domains contribute toward both the efficiency and specificity of viral genomic RNA packaging.
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PMID:Nucleocapsid protein effects on the specificity of retrovirus RNA encapsidation. 763 17

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.
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PMID:WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. 794 79

The nucleocapsid protein of Moloney murine leukemia virus (NCp10) is a 56-amino acid protein which contains one zinc finger of the CysX2CysX4HisX4Cys form, a highly conserved motif present in most retroviruses and retroelements. At pH > or = 5, NCp10 binds one zinc atom and the complexation induces a folding of the CysX2CysX4HEsX4Cys box, similar to that observed for the zinc-binding domains of HIV-1 NC protein. The three-dimensional structure of NCp10 has been determined in aqueous solution by 600 MHz 1H NMR spectroscopy. The proton resonances could be almost completely assigned by means of phase-sensitive double-quantum-filtered COSY, TOCSY and NOESY techniques. NOESY spectra yielded 597 relevant structural constraints, which were used as input for distance geometry calculations with DIANA. Further refinement was performed by minimization with the program AMBER, which was modified by introducing a zinc force field. The solution structure is characterized by a well-defined central zinc finger (rmsd of 0.747 +/- 0.209 A for backbone atoms and 1.709 +/- 0.187 A when all atoms are considered), surrounded by flexible N- and C-terminal domains. The Tyr28, Trp35, Lys37, Lys41 and Lys42 residues, which are essential for activity, lie on the same face of the zinc finger, forming a bulge structure probably involved in viral RNA binding. The significance of these structural characteristics for the various biological functions of the protein is discussed, taking into account the results obtained with various mutants.
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PMID:Three-dimensional 1H NMR structure of the nucleocapsid protein NCp10 of Moloney murine leukemia virus. 801 31

The CT/GC-rich region (-76 to -47) is one transcriptional regulatory region of the interleukin-3 (IL-3) gene which confers basic transcriptional activity and responds to trans-activation by human T-cell leukemia virus type I-encoded Tax. We isolated three types of cDNAs encoding Cys2/His2-type zinc finger proteins that bind to this region. Two were identical to known transcription factors, EGR1 and EGR2, and the other clone, named DB1, encoded a novel protein of 516 amino acids with six zinc finger motifs. DB1 mRNA was present in human tissues, ubiquitously. Two constitutive transcripts of 4.0 and 4.8 kb in length were present in Jurkat cells. Electrophoretic mobility shift assay, with specific antibodies, showed that DB1 constitutively binds to this region whereas EGR1 binds in a T-cell activation-dependent manner. Overexpression of DB1 in Jurkat cells had no detectable effect on the transcription activity of the IL-3 promoter, in a transient-transfection assay. EGR1 and EGR2 increased IL-3 promoter activity when the transfected cells were stimulated with phorbol-12-myristate-13-acetate and A23187. When DB1 was cotransfected with a Tax expression vector, transcription activity of the IL-3 promoter induced by Tax was significantly increased, while EGR1 and EGR2 were without effect. These results suggest that EGR1 has a role in inducible transcription of the IL-3 gene, while DB1 sustains basal transcriptional activity and also cooperates with Tax to activate the IL-3 promoter.
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PMID:Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the interleukin-3 promoter. 803 92

Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) that results in the fusion of the retinoic acid receptor alpha (RAR alpha) gene with a transcription factor gene called PML. Several cases of APML with t(11;17) have recently been described, involving fusion of the RAR alpha gene with a new zinc finger gene named PLZF. We report here a second non-classical translocation, t(5;17), with a rearranged RAR alpha gene in a child with APML. Based on restriction endonuclease analysis, the rearrangement of RAR alpha occurred within the second intron, the common breakpoint site for t(15;17). The leukemic cells in the bone marrow aspirate were a mixture of hypergranular and hypogranular bilobed promyelocytes. Although less than 1% abnormal promyelocytes were identified after induction therapy, cytogenetics revealed persistent t(5;17). Therefore, the child was treated with all-trans-retinoic acid (ATRA). There was no disease progression, and one marrow was interpreted as remission, with confirmation by cytogenetics which failed to reveal the translocation. However, disease reoccurred shortly after completion of ATRA. This poor response to ATRA may be an additional characteristic associated with non-classical translocations in APML. The identification of a second variant translocation involving the RAR alpha gene in APML suggests yet another RAR alpha rearrangement related to neoplastic myelopoiesis.
Leukemia 1994 Aug
PMID:A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features. 805 72

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