Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Ascorbyl radical (ASR) in human cerebrospinal fluid (CSF) of various patients using electron paramagnetic resonance (EPR) at ambient temperature was investigated. Also, effect of chemotherapy on ASR as well as ascorbate (ASA) in CSF and serum of acute lymphoblastic leukemia (ALL) was studied. EPR spectra of various CSF samples showed a characteristic doublet, which was attributed to ASR. ASR in CSF and serum was directly measured without any chemical modification. ASA and ASR concentration in CSF were approximately two times higher than those in serum. ASA and ASR concentrations in CSF and serum were statistically analyzed. The analyses showed that ASR and ASA in CSF and serum had good correlation for patients undergoing chemotherapy but not for patients after the therapy. The correlation for ASR and ASA suggests that ascorbate may play an important role during chemotherapy. In addition, dynamic aspects of ASA and ASR in CSF and serum are discussed.
Cell Mol Biol (Noisy-le-grand) 2000 Dec
PMID:Effect of chemotherapy on ascorbate and ascorbyl radical in cerebrospinal fluid and serum of acute lymphoblastic leukemia. 1115 82

To elucidate molecular mechanism(s) of cellular response to mercaptopurine, a widely used antileukemic agent, we assessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and MMR deficient human acute lymphoblastic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e., MutSalpha) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear extracts from ALL cells with synthetic 34-mer DNA duplexes containing deoxythioguanosine (G(S)) within either G(S).T or G(S).C pairs, resulted in formation of a DNA-protein complex distinct from the DNA-MutSalpha complex and unaffected by ATP. Isolation and sequence analysis of proteins involved in this DNA-protein complex identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a component. Western blot analysis of nuclear extracts from a panel of human lymphoblastic leukemia cell lines revealed markedly different basal levels of GAPDH in nuclei, which was significantly related to thiopurine sensitivity (p = 0.001). Confocal analysis revealed markedly different intracellular distribution of GAPDH between nucleus and cytosol in six human ALL cell lines. Redistribution of GAPDH from cytosol to nucleus was evident after MP treatment. These findings indicate that a new DNA-protein complex containing GAPDH and distinct from known MMR protein-DNA complexes binds directly to thioguanylated DNA, suggesting that this may act as a sensor of structural alterations in DNA and serve as an interface between these DNA modifications and apoptosis.
Mol Pharmacol 2001 Feb
PMID:A novel protein complex distinct from mismatch repair binds thioguanylated DNA. 1116 Aug 74

To determine whether subendothelial laminins (LNs) could be implicated in the extravasation of neoplastic lymphocytes, we have examined the distribution of a number of LN isoforms in human vascular structures of adult individuals and have assayed the ability of the isolated LN molecules to promote adhesion of lymphoma and leukemic cells in vitro using a novel cell adhesion assay, CAFCA, Centrifugal Assay for Fluorescence-based Cell Adhesion (E. Giacomello et al., Biotechniques, 26: 758-762, 1999; P. Spessotto et al., Methods Mol. Biol., 139: 321-343, 2000). The use of previously characterized LN chain-specific antibodies showed that the vast majority of the smaller vascular compartments, known to correspond to sites of lymphocyte transmigration, expressed the subunits involved in the structuring of 9 of the 12 LN isoforms known to date. Eight LN isoforms (i.e., LN-1, -2, -4, -5, -8, -9, -10, and -11) and four naturally occurring LN complexes were isolated from various tissues and cultured cells by combined gel filtration, ion exchange, and immunoaffinity chromatographies, and the identity/composition of the isolated LNs/LN complexes was asserted by immunochemical means and amino-acid sequencing. Notwithstanding the widespread colocalization of LN isoforms, a panel of neoplastic B- and T-cell lines and lymphocytes isolated from patients affected by chronic lymphocytic B-cell leukemia attached preferentially and with high avidity to purified LN-8, purified LN-10, and LN-10-containing protein complexes, whereas lymphocytes derived from patients diagnosed with acute lymphocytic leukemia failed to bind to these LNs. All of the tested neoplastic lymphocytes failed to adhere to the isolated LN-1, LN-4, LN-9, and LN-11 and attached moderately well to purified LN-2 and LN-5. The interaction of transformed lymphocytes with LNs was cation-dependent and interchangeably mediated by the alpha3beta1 and alpha6beta1 integrins. The degree of engagement of the two LN receptors was dependent upon their relative levels of cell surface expression, whereas, irrespective of the phenotype, lymphocytes deprived of either of these receptors were incapable of LN binding. The findings suggest that LN-8 and LN-10 may act in an independent or complementary fashion as primary components of the endothelial basement membrane favoring the interaction of extravasating neoplastic lymphocytes. Thus, our results would demonstrate that different LN isoforms may evoke diverse cellular responses in different cell types and that this divergence may be the basis for the redundancy of LN distribution in a number of vascular structures.
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PMID:Laminin isoforms 8 and 10 are primary components of the subendothelial basement membrane promoting interaction with neoplastic lymphocytes. 1119 84

The Bcr/Abl P190 oncoprotein is responsible for the development of Philadelphia-chromosome positive acute lymphoblastic leukemia (ALL). The Bcr moiety in Bcr/Abl activates the Abl tyrosine kinase, an ingredient essential for the transforming capability of Bcr/Abl. Residues 1-63 of Bcr form an N-terminal oligomerization domain and are key to Abl activation in vitro. Mice transgenic for P190 BCR/ABL reproducibly develop an aggressive B-lineage lymphoblastic leukemia/lymphoma. Here we test the hypothesis that residues 1-63 of Bcr have a major in vivo contribution to the oncogenicity of Bcr/Abl P190 by the generation of mice transgenic for an N-terminal deleted form of P190. We find that although the transgene is expressed in the bone marrow of mice at an early age, the incidence of leukemogenesis is greatly diminished as compared to mice transgenic for non-mutated P190 Bcr/Abl. Sporadic hematological malignancies which did develop showed decreased levels of phosphotyrosine as compared to those of wild-type P190 transgenics, although Ras was activated. These results demonstrate that the Bcr oligomerization domain contributes to the oncogenicity of Bcr/Abl in vivo.
Int J Mol Med 2001 Apr
PMID:The Bcr N-terminal oligomerization domain contributes to the full oncogenicity of P190 Bcr/Abl in transgenic mice. 1125 72

p210bcr/abl is detected in almost all chronic myelogenous leukemia (CML) patients and a significant number of acute lymphoblastic leukemia (ALL) cases. It is generated by a reciprocal chromosomal translocation, t(9;22) (q34;q11), and the enhanced kinase activity of the protein is believed to be implicated in the pathogenesis of the diseases. To examine its oncogenicity in vivo and to create an animal model for BCR/ABL-positive leukemias, we generated transgenic mice expressing p210bcr/abl driven by the promoter of the mouse tec gene, a cytoplasmic tyrosine kinase preferentially expressed in early hematopoietic progenitors. While the founder mice showed excessive proliferation of lymphoblasts shortly after birth and were diagnosed as ALL, the transgenic progeny reproducibly exhibited marked granulocyte hyperplasia with thrombocytosis after a long latent period, which closely resembles the clinical course of human CML. In addition, to investigate whether loss of p53 would play a role in the transition from chronic phase to blast crisis of CML, we crossmated p210bcr/abl transgenic (BCR/ABLtg/-) mice with p53 heterozygous (p53+/-) mice and generated p210bcr/abl transgenic, p53 heterozygous (BCR/ABLtg/- p53+/-) mice, in which a somatic alteration in the residual p53 allele directly abrogates p53 function. The BCR/ABLtg/- p53+/- mice exhibited rapid proliferation of blast cells and died in a short period compared with their wild-type (BCR/ABL-/- p53+/+), p53 heterozygous (BCR/ABL-/- p53+/-), and p210bcr/abl transgenic (BCR/ABLtg/- p53+/+) littermates. Interestingly, the normal p53 allele was frequently and preferentially lost in the tumor tissues, providing in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210bcr/abl-expressing hematopoietic cells. Our transgenic mice will be a useful model for investigating oncogenic properties of p210bcr/abl in vivo and will provide insights into the molecular mechanism(s) underlying the progression from chronic phase to blast crisis of CML.
Blood Cells Mol Dis
PMID:Model mice for BCR/ABL-positive leukemias. 1135 87

CD79 is composed of CD79a and CD79b components expressed almost exclusively on B cells and B-cell neoplasms. CD79a and CD79b expression precedes immunoglobulin (Ig) heavy-chain gene rearrangement and CD20 expression during B-cell ontogeny and disappears later than CD20 in the late (plasma cell) stage of B-cell differentiation. Therefore, antibodies to CD79a and CD79b are useful in the differential diagnosis of B-cell neoplasms from T-cell neoplasms or myeloid neoplasms, or L and H lymphocyte predominance Hodgkin's lymphoma from classic Hodgkin's lymphoma. In addition, CD79a and CD79b antibodies are useful markers in the diagnosis of precursor B-acute lymphoblastic leukemia (pre-B-ALL) because many of these tumors are negative for other B-cell markers, such as CD20 and CD45RA. Furthermore, for B-cell neoplasms, wherein CD20 expression is aberrantly lost, such as in diffuse large B-cell lymphoma, or for B-cell neoplasms after CD20-antibody therapy, CD79a may be used as a first-line B-cell marker for the diagnosis. In this review, the authors discuss the molecular biology of CD79 and the frequency and usefulness of CD79 expression in these neoplasms.
Appl Immunohistochem Mol Morphol 2001 Jun
PMID:CD79: a review. 1139 39

The Ces-2/E2A-HLF binding element (CBE) is recognized by Caenorhabditis elegans death specification gene product Ces-2 and human acute lymphocytic leukemia oncoprotein E2A-HLF. In an attempt to identify a cellular CBE-binding protein(s) that may be involved in apoptosis regulation in mammals, multiple nuclear binding complexes of CBE were identified in various mammalian cell lines and tissues by electrophoretic mobility shift assay. Cyclic AMP (cAMP)-responsive element (CRE)-binding protein (CREB) was present in one major CBE complex of Ba/F3 and TF-1 cells, and both in vitro-translated and Escherichia coli-synthesized CREB bound to CBE. Activation of CREB by cAMP-elevating chemicals or the catalytic subunit of protein kinase A (PKAc) resulted in induction of the CBE-driven reporter gene. Stimulation of Ba/F3 cells with interleukin-3 (IL-3) promptly induced phosphorylation of CREB at serine(133) partially via a PKA-dependent pathway. Consistently, Ba/F3 cell survival in the absence of IL-3 was prolonged by activation of PKA. Conversely, treatment of cells with a PKA inhibitor or expression of the dominant negative forms of the regulatory subunit type I of PKA and CREB overrode the survival activity of IL-3. Last, the bcl-2 gene was demonstrated to be one candidate cellular target of the CREB-containing CBE complex, as mutations in the CRE and CBE sites significantly reduced the IL-3 inducibility of the bcl-2 promoter. Together, our results suggest that CREB is one cellular counterpart of Ces-2/E2A-HLF and is part of IL-3 dependent apoptosis regulation in hematopoietic cells.
Mol Cell Biol 2001 Jul
PMID:CREB is one component of the binding complex of the Ces-2/E2A-HLF binding element and is an integral part of the interleukin-3 survival signal. 1141 41

There is increasing interest in changing the emphasis of tumor classification from morphologic to molecular. Gene expression profiles may offer more information than morphology and provide an alternative to morphology-based tumor classification systems. Gene selection involves a search for gene subsets that are able to discriminate tumor tissue from normal tissue, and may have either clear biological interpretation or some implication in the molecular mechanism of the tumorigenesis. Gene selection is a fundamental issue in gene expression-based tumor classification. In the formation of a discriminant rule, the number of genes is large relative to the number of tissue samples. Too many genes can harm the performance of the tumor classification system and increase the cost as well. In this report, we discuss criteria and illustrate techniques for reducing the number of genes and selecting an optimal (or near optimal) subset of genes from an initial set of genes for tumor classification. The practical advantages of gene selection over other methods of reducing the dimensionality (e.g., principal components), include its simplicity, future cost savings, and higher likelihood of being adopted in a clinical setting. We analyze the expression profiles of 2000 genes in 22 normal and 40 colon tumor tissues, 5776 sequences in 14 human mammary epithelial cells and 13 breast tumors, and 6817 genes in 47 acute lymphoblastic leukemia and 25 acute myeloid leukemia samples. Through these three examples, we show that using 2 or 3 genes can achieve more than 90% accuracy of classification. This result implies that after initial investigation of tumor classification using microarrays, a small number of selected genes may be used as biomarkers for tumor classification, or may have some relevance in tumor development and serve as a potential drug target. In this report we also show that stepwise Fisher's linear discriminant function is a practicable method for gene expression-based tumor classification.
Mol Genet Metab 2001 Jul
PMID:Feature (gene) selection in gene expression-based tumor classification. 1146 Nov 91

PBK/TOPK is a recently cloned serine/threonine kinase which is phosphorylated during mitosis. Earlier work indicated that this kinase is upregulated in a Burkitt's lymphoma cell line (GA-10). To determine whether PBK/TOPK is upregulated in other mitotically active neoplastic cell lines and tissues, Northern analysis was performed on a panel of malignant cell lines and on clinical samples from patients with leukemia or lymphoma. While PBK/TOPK mRNA was not detectable in normal peripheral blood cells and was weakly expressed in hyperplastic tonsillar B-cells, significantly higher levels of mRNA were detected in 8 Burkitt's lymphoma cell lines, 10 other neoplastic cell lines, and 2 clinical samples-one derived from a patient with ALL and a second derived from a patient with relapsed myeloma. In addition, Northern analysis of fetal tissues showed upregulated expression of PBK/TOPK in fetal kidney, lung, spleen, brain, and testis. These data suggest that PBK/TOPK expression is increased in highly proliferative malignant cells and during normal fetal development.
Blood Cells Mol Dis
PMID:PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells. 1178 45

Approximately 80% of children with acute lymphoblastic leukemia (ALL) can be cured with modern therapy. Despite this success, the number of cases of relapsed ALL remains greater than the number of new cases of most childhood cancers. New strategies are needed to develop curative therapy for the 20% of patients who are not being cured today, and to develop less toxic and less onerous treatment for ALL patients. Molecular genetics has already provided important insights to the mechanisms of leukemogenesis and is now routinely used to define the prognosis and guide treatment intensity for childhood ALL. Pharmacogenomics is a burgeoning field that aims to elucidate inherited differences in drug disposition and treatment response, toward individualizing therapy to enhance efficacy and reduce toxicity. Herein, we review recent progress in thesefields as they relate to childhood ALL, and discuss the promise they hold to further enhance treatment of the most common cancer in children.
Curr Opin Mol Ther 2001 Dec
PMID:Pharmacogenomics of childhood acute lymphoblastic leukemia. 1180 71


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