Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tax is a transcription activator encoded by human T-cell leukemia virus (HTLV)-1. Ribosomal protein L6 was also defined as Taxreb107 (Tax responsible element binding protein 107) for its activity of binding to the long terminal repeats of HTLV-1. To investigate the relationship between Tax and Taxreb107/RpL6, yeast two hybrid and GST pull-down assays were used. Results suggest that Tax can interact with Taxreb107/RpL6 directly and Taxreb107/RpL6 may regulate the function of Tax in HTLV-1 proliferation.
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PMID:[Interaction between HTLV-1 transcription activator tax and Taxreb107]. 1200 2

Donor lymphocyte infusion (DLI) reliably induces durable remission in 75-80% of patients with relapsed chronic myelogenous leukemia (CML) after allogeneic hematopoietic stem cell transplantation. To identify immunological targets of the graft-versus-leukemia response (GVL) after DLI, we used CML post-DLI responder sera to screen a CML cDNA expression library. One of the antigens identified in this screen is a M(r) 28,000 protein, termed CML28. CML28 is identical to hRrp46p, a component of the human exosome, a multiprotein complex involved in the 3' processing of RNA. Components of the human exosome include known autoantigens, such as PMScl-100, an autoantibody target in patients with polymyositis, scleroderma, or polymyositis-scleroderma overlap syndrome. Recombinant CML28-GST fusion protein was purified, and used in Western blot and ELISA to demonstrate the development of a high-titer CML28-specific IgG antibody response in a patient with relapsed CML who responded to DLI. Northern blotting demonstrated that CML28 is highly expressed in a variety of hematopoietic and epithelial tumor cell lines, but not in normal hematopoietic tissues or other normal tissue, with the exception of testis. Purified recombinant CML28 was used to generate a CML28-specific murine monoclonal antibody. Western blotting with CML28 monoclonal antibody against whole-cell lysates derived from blood and marrow of normal donors and patients with leukemia revealed high expression of this antigen in tumor but not in normal samples. Because CML28 was highly expressed in epithelial tumor cell lines, anti-CML28 responses were also examined in patients with solid tumors. By ELISA, we found specific serological responses in 10-33% of patients with lung cancer, melanoma, and prostate cancer. Our studies suggest that immunogenicity of CML28 is likely because of overexpression of this antigen in tumor cells. Moreover, given its expression and immunogenicity in a wide variety of malignancies, CML28 merits additional evaluation as a target for antigen-specific immunotherapy.
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PMID:CML28 is a broadly immunogenic antigen, which is overexpressed in tumor cells. 1235 62

Glutathione S-transferase pi (GSTP1) is involved in the metabolism of carcinogens. We assessed the association of GSTP1 genetic polymorphisms and the susceptibility to childhood acute lymphoblastic leukaemia (ALL) by conducting a case-control study on 278 ALL patients and 303 healthy controls, both of French-Canadian origin. The carriers of the GSTP1*B variant (only the Val105 substitution) were found to be associated with an increased risk of ALL [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.0], whereas the GSTP1*C variant (both Val105 and Val114) was underrepresented in cases. Thus, genetic variants of GSTP1 that are expressed at the protein level appear to contribute differently to the risk of ALL, probably because of distinct substrate specificities. When combined with other GST genotypes, we found that the combination of GSTP1*B and GSTM1 null genotypes further increased the risk of ALL (OR = 2.1; 95% CI-1.3-3.4). These findings suggest that GSTP1 variants (alone or combined with other GSTs) represent significant genetic determinants of childhood ALL.
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PMID:Glutathione S-transferase P1 genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukaemia. 1243 26

Benzene is one of wildly used chemicals. Long-term exposure to benzene causes hematotoxicities and further, the development of including anemia, myelodysplastic syndrome (MDS), aplastic anemia, etc., with the leukemia as the worst. People vary greatly in their susceptibility to adverse health outcomes from benzene exposure. The author reviewed the relationship between genetic polymorphism of I metabolic enzymes(CYP2E1, NQO1, MPO) and II metabolic enzymes(GST, PST) involving benzene metabolite and interindividual variation in their genetic susceptibility to hematotoxicity from benzene exposure in this paper.
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PMID:[Individual susceptibility to hematotoxicity from benzene exposure and the genetic polymorphism of metabolic enzymes]. 1256 53

Among mechanisms potentially involved in resistance to alkylating agents and anthracyclines, the glutathione system has been extensively studied in vitro. We analyzed by immunohistochemistry the relation between glutathione s-transferase pi (GST-pi) expression in tumor cells and outcome in 69 cases of diffuse large B-cell NHL (DLBCL). GST-pi expression was considered as low when <50% of tumor cells were stained and high when >/=50% tumor cells were stained. Median follow-up was 58 months. GST-pi expression was correlated with the probability of achieving complete remission (CR). Patients with high GST-pi expression had a worse 5-year freedom from progression (FFP). High GST-pi expression was associated with a trend for lower survival. In the group of patients with International Prognostic Index (IPI) 0-1, low GST-pi expression was associated with a CR rate of 88%, a 5-year FFP of 76+/-20% and a 5-year survival of 78+/-16% compared to 36, 14+/-16 and 40+/-32%, respectively, in patients with a high GST-pi expression (P=0.002, P&<10(-5) and P=0.01, respectively). No correlation was found between GST-pi expression and lactico deshydrogenase serum level, age, Ann Arbor stage, performance status, and IPI index. Both GST-pi expression and the IPI index correlated with FFP. After incorporating IPI and GST-pi expression in a multivariate analysis for FFP, GST-p expression remained the only prognostic factor (P=0.003). Our findings suggest that GST-pi expression had strong prognostic significance in DLBCL, which appears to be independent of other prognostic parameters in those disorders.
Leukemia 2003 May
PMID:Prognostic value of GST-pi expression in diffuse large B-cell lymphomas. 1275 Jul 12

The amount of MSH2 protein, a major component of the mismatch repair system, was found to differ >10-fold in leukemia cells from children with newly diagnosed acute lymphoblastic leukemia, with a subgroup of patients (17%) having undetectable MSH2 protein. We therefore used a murine Msh2 knockout model to elucidate the in vivo importance of MSH2 protein expression in determining thiopurine hematopoietic cytotoxicity. After mercaptopurine (MP) treatment (30 mg/kg/day for 14 days), there was a significantly greater decrease in circulating leukocytes in Msh2+/+ and Msh2+/- mice when compared with Msh2-/- mice (p < 0.002). Likewise, the decrease in erythrocyte counts was more prominent in mice with at least one functional Msh2 allele. MP doses of more than 50 mg/kg/day for 14 days resulted in treatment-related deaths, but Msh2-/- mice had a significant survival advantage (p = 0.02). Murine embryonic fibroblasts (MEFs) from Msh2+/+ mice also exhibited increased sensitivity to MP when compared with MEFs from Msh2-/- mice (IC50, 3.8 +/- 0.1 microM versus 11.9 +/- 1.3 microM, p < 0.001). After MP treatment, deoxythioguanosine incorporation into DNA was similar in mice and MEFs with each of the Msh2 genotypes. Electromobility shift assay experiments identified an Msh2-containing GT- or GST-DNA-nuclear protein complex in Msh2+/+ but not Msh2-/- MEFs. Together, these findings establish that hematopoietic toxicity in vivo after treatment with mercaptopurine is attenuated but not abolished by MSH2 deficiency.
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PMID:Msh2 deficiency attenuates but does not abolish thiopurine hematopoietic toxicity in msh2-/- mice. 1286 51

Phosphatase in activated T cells (PAC-1) is a mitogen-induced early responsive gene. It encodes a 32 kDa tyrosine-threonine dual specificity phosphatase. Constitutive expression of PAC-1 leads to an inhibition of MAP kinase activity in vivo. Such constitutive expression was reported in HTLV-1 infected cell lines. In the present study, we observed the constitutive over-expression of two transcripts related to PAC-1 in large granular lymphocyte (LGL) leukemia. By screening a LGL leukemia cDNA library using the 3' end of a PAC-1 probe, we obtained a clone (clone 8) which retains one and one half introns, excludes two exons, and matches one hundred percent with a DNA sequence on chromosome 2. The deduced amino acid sequence of the predicted protein contains 170 amino acids and is 144 amino acids shorter than PAC-1. When we expressed this protein in Escherichia coli as a GST-fusion protein, a 45 kDa (19 kDa PAC-1 variant+26 kDa GST protein) protein was obtained. The expressed protein was purified to near homogeneity by using a glutathione affinity column. The purified protein did not have any intrinsic phosphatase activity when assayed in vitro. But when this purified protein was added to a phosphatase assay system in combination with a recombinant dual specificity phosphatase, CL100, enhanced phosphatase activity was observed. The significance of the constitutive over-expression and its physiological role of this protein remain to be established in leukemic LGL.
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PMID:Characterization of a variant of PAC-1 in large granular lymphocyte leukemia. 1468 Sep 39

PLZF, the promyelocytic leukaemia zinc-finger protein, is a transcriptional repressor essential to development. In some acute leukaemias, a chromosomal translocation fusing the PLZF gene to that encoding the retinoic acid receptor RARalpha gives rise to a fusion protein, PLZF-RARalpha, thought to be responsible for constitutive repression of differentiation-associated genes in these cells. Repression by both PLZF and PLZF-RARalpha is sensitive to the histone deacetylase inhibitor TSA, and PLZF was previously shown to interact physically with HDAC1, a class I histone deacetylase. We here asked whether class II histone deacetylases, known to be generally involved in differentiation processes, participate in the repression mediated by PLZF and PLZF-RARalpha, and found that PLZF interacts with HDAC4 in both GST-pull-down and co-immunoprecipitation assays. Furthermore, HDAC4 is indeed involved in PLZF and PLZF-RARalpha-mediated repression, since an enzymatically dead mutant of HDAC4 released the repression, as did an siRNA that blocks HDAC4 expression. Taken together, our data indicate that recruitment of HDAC4 is necessary for PLZF-mediated repression in both normal and leukaemic cells.
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PMID:HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF. 1546 36

T-cell large granular lymphocyte (T-LGL) leukemia is a rare chronic lymphoproliferative disorder of unknown etiology. We have previously reported that patients with T-LGL leukemia were seroreactive against BA21, a 34 amino acid peptide derived from HTLV-I envelope protein p21. We tested sera from 70 patients with T-LGL leukemia and found that 21/70 (30%) of them were seroreactive against fusion peptide GST-BA21. In control group of healthy blood donors 3/30 (10%) were seroreactive. We synthesized a set of overlapping peptides derived from BA21 and tested them against sera from patients. Only a single peptide (p21 env 417-430) showed reactivity. We then generated multiple fusion peptides consisting of 5-14 amino acid residues derived from this peptide and tested them against patient and control sera. Shortest peptide giving positive seroreactivity was octapeptide P8 (p21 env 418-425). Competitive Western blot assay with use of fusion peptides revealed that the minimal HTLV-I epitope responsible for seroreactivity found in patients with T-LGL leukemia is a decapeptide PP10 (p21 env 417-426). Protein Bank (NCBI) search did not reveal any significant homology between PP10 epitope and known human proteins. These results further define the epitope responsible for HTLV env seroreactivity observed in LGL leukemia.
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PMID:Characterization of HTLV envelope seroreactivity in large granular lymphocyte leukemia. 1572 71

Mixed lineage leukemia (MLL) fusion proteins are derived from translocations at 11q23 that occur in aggressive subtypes of leukemia. As a consequence, MLL is joined to different unrelated proteins to form oncogenic transcription factors. Here we demonstrate a direct interaction between several nuclear MLL fusion partners and present evidence for a role of these proteins in histone binding. In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10. A structure-function analysis revealed that the AF4/AF5q31/AF10 binding domain in ENL coincided with the C-terminus that is essential for transformation by MLL-ENL. The ENL/AF4 association was corroborated by GST-pulldown experiments and by mutual coprecipitation. Both proteins colocalized in vivo in a nuclear speckled pattern. Moreover, AF4 and ENL coeluted on sizing columns together with the known ENL binding partner Polycomb3, suggesting the presence of a multiprotein complex. The overexpression of ENL alone activated a reporter construct and a mutational screen indicated the conserved YEATS domain as essential for this function. Overlay and pulldown-assays finally showed a specific and YEATS domain-dependent association of ENL with histones H3 and H1. In summary, our studies support a common role for nuclear MLL fusion partners in chromatin biology.
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PMID:The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. 1585 11


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