Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FRAT1 positively regulates the WNT signaling pathway by stabilizing beta-catenin through the association with glycogen synthase kinase-3beta. Here, we have cloned FRAT2 cDNAs, spanning the complete coding sequence, from a human fetal lung cDNA library. FRAT2 encoded 233 amino-acid protein, which showed 77.3% total amino-acid identity with FRAT1. FRAT2 and FRAT1 were more homologous in the acidic domain (96% identity), the proline-rich domain (92% identity), and the GSK-3beta binding domain (100% identity). The FRAT2 gene was mapped to human chromosome 10q24.1. The FRAT2 mRNA of 2.4-kb in size was relatively highly expressed in MKN45 (gastric cancer), HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia). Xenopus axis duplication assay revealed that the wild-type FRAT2 mRNA, but not the mutant FRAT2 mRNA lacking the acidic domain and the proline-rich domain, has the capacity to induce the secondary axis. These results indicate that FRAT2, just like FRAT1, functions as a positive regulator of the WNT signaling pathway. Thus, up-regulation of FRAT2 in human cancer might be implicated in carcinogenesis through activation of the WNT signaling pathway.
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PMID:Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway. 1123 32

Hfz5 is a potent cancer associated gene, encoding WNT receptor with the potential to activate beta-catenin - TCF signaling pathway. Here, human Frizzled-5 (FZD5) gene and cDNAs were cloned and characterized. FZD5 was almost identical to Hfz5, except for six amino-acid substitutions at codon 88, 262, 263, 345, 357, and 402. HF5S1 probe (nucleotide position 2036-2535 of FZD5 cDNA) hybridized to 7.5- and 3.5-kb FZD5 mRNAs, and HF5S2 probe (nucleotide position 5572-6194 of FZD5 cDNA) hybridized only to 7.5-kb FZD5 mRNA. FZD5 cDNA was polyadenylated at the nucleotide position 6534, while several FZD5 ESTs were polyadenylated at the nucleotide position 2561. The 7.5- and 3.5-kb FZD5 mRNAs were transcribed probably due to alternative splicing. FZD5 was highly expressed in fetal liver and adult pancreas, and moderately expressed in fetal lung, kidney and adult liver. Among human cancer cell lines, FZD5 was highly expressed in K-562 cells derived from chronic myelogenous leukemia. FZD5 gene, consisting of two exons, was mapped to human chromosome 2q33.3-q34 region, near the FZD7 gene and the FRA2I fragile site. These results suggest that FZD5 up-regulation might play key roles in chronic myelogenous leukemia through activation of the WNT - beta-catenin - TCF signaling pathway.
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PMID:Molecular cloning and characterization of human Frizzled-5 gene on chromosome 2q33.3-q34 region. 1140 29

FRAT1 and FRAT2 are cancer-associated genes encoding GSK-3beta-binding proteins. Over-expression of FRAT1 or FRAT2 lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway. We have previously cloned and characterized FRAT2. Here, we found that FRAT1 and FRAT2 genes were clustered in the human chromosome 10q24.1 region. Blast search revealed that FRAT1 and FRAT2 genes, consisting of a single exon, were located together on human genome draft sequences AC006098.1 and AL355490.7, corresponding to the human chromosome 10q24.1 region. FRAT1 and FRAT2 genes were clustered in a tail to tail manner with an interval of about 10.7 kb. The 2.7-kb FRAT1 mRNA was relatively highly expressed in fetal brain, adult spleen, pancreas, HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia). FRAT1 and FRAT2 were co-expressed in 7 gastric cancer cell lines and 10 cases of primary gastric cancer, and were up-regulated together in gastric cancer cell line TMK1 and 2 cases of primary gastric cancer. These results indicated that FRAT1 and FRAT2 genes were up-regulated together in several cases of human gastric cancer. Up-regulation of FRAT1 and FRAT2 in gastric cancer might lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway.
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PMID:FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. 1144 44

Xenopus Strabismus (Stbm) is a negative regulator of the WNT - beta-catenin signaling pathway. Strabismus 1 (STB1/VangL2) and Strabismus 2 (STB2/Vangl1) are human homologues of Xenopus Stbm and Drosophila Stbm/ Van Gogh (Vang) STB1 and STB2 are four-transmembrane-type proteins with Dishevelled-binding motif. STB2 and CASQ2 genes are located on human chromosome 1p13.3-p11 with an interval less than 5 kb. Here, STB1 gene and CASQ1 gene were found to be located on human chromosome 1q21-q23 with an interval of about 210 kb including Nicastrin, COPA, PXF, H326 and PEA15 genes. Exon-intron structure was well conserved between STB1 and STB2 genes. STB1-CASQ1 gene cluster and STB2-CASQ2 gene cluster might be generated due to duplication of ancestral gene cluster, and several genes might be inserted into the STB1-CASQ1 intergenic region during or after gene-cluster duplication. STB1 mRNA was relatively highly expressed in prostate, trachea, thymus, lymph node, placenta, fetal kidney, fetal brain, and fetal lung. In adult brain, STB1 mRNA was more highly expressed in cerebellum, corpus callosum, amygdala, and medulla oblongata. STB1 mRNA was moderately expressed in K-562 (chronic myelogenous leukemia), G-361 (melanoma), and MKN7 (gastric cancer). On the other hand, STB1 mRNA was almost undetectable in several human cancer cell lines, and was down-regulated in 4 out of 14 cases of primary kidney tumors, and in 2 out of 3 cases of primary lung cancer. Loss-of-function mutation of STB1 gene might lead to carcinogenesis through activation of the WNT - beta-catenin signaling pathway.
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PMID:Structure and expression of Strabismus 1 gene on human chromosome 1q21-q23. 1201 99

The role of beta-catenin in epithelial neoplasms has been widely studied whereas current knowledge regarding beta-catenin gene and protein expression in bone marrow cells derived from normal haematopoiesis and clonal haematological disorders is lacking. beta-Catenin gene expression was quantitatively investigated in bone marrow cells derived from clonal haematological disorders [acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML], Ph- myeloproliferative disorders, n = 96) compared with non-neoplastic haematopoiesis (n = 33) by real-time reverse transcription polymerase chain reaction. Cellular localization of beta-catenin protein was detected by immunocytochemistry. beta-Catenin gene expression was significantly increased in AML compared with ALL cases (P < 0.0001), Ph+ CML (P < 0.0001) and non-neoplastic haematopoiesis (P = 0.019). Immunocytochemistry revealed that, in non-neoplastic haematopoiesis, the granulopoietic lineage as well as megakaryocytes showed membranous and cytoplasmic staining to various degrees along with unlabelled nuclei. Besides haematopoiesis, beta-catenin prominently marked bone marrow vascularity and diverse stroma cells. beta-Catenin gene was inversely expressed in AML and ALL with a lack of protein expression in neoplastic cells in ALL. In contrast, the other haematological disorders under study, except for Ph+ CML, did not show significant alterations of overall beta-catenin gene expression compared with normal bone marrow. These data suggest different regulatory mechanisms in the expression and function of beta-catenin in haematopoietic cells.
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PMID:Aberrant expression of beta-catenin discriminates acute myeloid leukaemia from acute lymphoblastic leukaemia. 1525 3

Cancer can be viewed as a hierarchical system that is dependent on a small population of "cancer stem cells" with unlimited self-renewal potential for continued growth and propagation of tumors. The identity and nature of these cells remains enigmatic, but an improved understanding of their biology may allow for selective therapeutic targeting. A recent report by sheds new light on leukemia stem cells by identifying the cells with in vitro self-renewing properties in various phases of chronic myelogenous leukemia, and linking the self-renewal properties of this population to activation of beta-catenin, a major effector of the canonical Wnt signaling pathway.
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PMID:Blasts from the past: new lessons in stem cell biology from chronic myelogenous leukemia. 1538 May 9

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease with distinct biological and clinical features. The biologic basis of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (P < 10(-10)) associated with phase of disease. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML to advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased numbers of leukemia blast cells. Especially noteworthy and potentially significant in the progression program were the deregulation of the WNT/beta-catenin pathway, the decreased expression of Jun B and Fos, alternative kinase deregulation, such as Arg (Abl2), and an increased expression of PRAME. Studies of CML patients who relapsed after initially successful treatment with imatinib demonstrated a gene expression pattern closely related to advanced phase disease. These studies point to specific gene pathways that might be exploited for both prognostic indicators as well as new targets for therapy.
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PMID:Gene expression changes associated with progression and response in chronic myeloid leukemia. 1647 19

Activation of the Wnt/beta-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P<0.05). Furthermore, variations in beta-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/beta-catenin pathway only in leukemic cells. Indeed, beta-catenin negative leukemic cells were found to increase beta-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.
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PMID:Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. 1668 29

Self-renewal of Bcr-Abl(+) chronic myeloid leukemia (CML) cells is sustained by a nuclear activated serine/threonine-(S/T) unphosphorylated beta-catenin. Although beta-catenin can be tyrosine (Y)-phosphorylated, the occurrence and biological relevance of this covalent modification in Bcr-Abl-associated leukemogenesis is unknown. Here we show that Bcr-Abl levels control the degree of beta-catenin protein stabilization by affecting its Y/S/T-phospho content in CML cells. Bcr-Abl physically interacts with beta-catenin, and its oncogenic tyrosine kinase activity is required to phosphorylate beta-catenin at Y86 and Y654 residues. This Y-phospho beta-catenin binds to the TCF4 transcription factor, thus representing a transcriptionally active pool. Imatinib, a Bcr-Abl antagonist, impairs the beta-catenin/TCF-related transcription causing a rapid cytosolic retention of Y-unphosphorylated beta-catenin, which presents an increased binding affinity for the Axin/GSK3beta complex. Although Bcr-Abl does not affect GSK3beta autophosphorylation, it prevents, through its effect on beta-catenin Y phosphorylation, Axin/GSK3beta binding to beta-catenin and its subsequent S/T phosphorylation. Silencing of beta-catenin by small interfering RNA inhibited proliferation and clonogenicity of Bcr-Abl(+) CML cells, in synergism with Imatinib. These findings indicate the Bcr-Abl triggered Y phosphorylation of beta-catenin as a new mechanism responsible for its protein stabilization and nuclear signalling activation in CML.
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PMID:Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. 1731 91

Deciphering the BCR-ABL-independent signaling exploited in chronic myeloid leukemia (CML) progression is an important aspect in cancer stem-cell biology. CML stem-cell compartment is dynamic as it progresses to terminal blast crisis where myeloid and lymphoid blasts fail to differentiate. We demonstrate cross-regulation of signaling network involving Sonic hedgehog (Shh), Wnt, Notch and Hox for the inexorable blastic transformation of CD34(+) CML cells. Significant upregulation in Patched1, Frizzled2, Lef1, CyclinD1, p21 (P < or =0.0002) and downregulation of HoxA10 and HoxB4 (P< or =0.0001) transcripts in CD34(+) cells distinguish blast crisis from chronic CML. We report Shh-dependent Stat3 activation orchestrates these mutually interconnected signaling pathways. Stimulation of CD34(+) CML cells with either soluble Shh or Wnt3a did not activate Akt or p44/42-mitogen activated protein kinase (MAPK) pathways. Interestingly, unlike dominant negative Stat3beta, introduction of constitutive active Stat3 in CD34(+) CML cells induces cross-regulation in gene expression. Additionally, Shh and Wnt3a-dependent regulation of cyclin-dependent kinase inhibitors (CDKI) in CML suggests their role in the network. Taken together, our findings propose that deregulation in the form of hyperactive Shh and Wnt with repressed Notch and Hox pathways involving Stat3, Gli3, beta-catenin, CyclinD1, Hes1, HoxA10 and p21 might act synergistically to form an important hub in CML progression.
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PMID:Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. 1736 Dec 18


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