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1.
Leuk Res ; 69: 24-30, 2018 06.
Article in English | MEDLINE | ID: mdl-29625321

ABSTRACT

Wnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia/metabolism , Wnt Proteins/antagonists & inhibitors , Wnt Signaling Pathway/drug effects , Hematologic Neoplasms/metabolism , Humans , Wnt Proteins/metabolism
2.
Tumour Biol ; 39(5): 1010428317701654, 2017 May.
Article in English | MEDLINE | ID: mdl-28468589

ABSTRACT

Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/ß-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/ß-catenin pathway antagonists-secreted frizzled-related protein 1 and Wnt inhibitory factor 1-on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia. Response to tyrosine kinase inhibitors was analyzed in secreted frizzled-related protein 1 and Wnt inhibitory factor 1 stably transfected K562 cells. Experiments were repeated using a tetracycline-inducible expression system, confirming previous results. In addition, response to tyrosine kinase inhibitor treatment was also analyzed using the secreted frizzled-related protein 1 expressing, BCR-ABL positive MEG01 cell line, in the presence and absence of a secreted frizzled-related protein 1 inhibitor. Our data suggests that total cellular ß-catenin levels decrease in the presence of secreted frizzled-related protein 1 and Wnt inhibitory factor 1, and a significant increase in cell death after tyrosine kinase inhibitor treatment is observed. On the contrary, when secreted frizzled-related protein 1 is suppressed, total ß-catenin levels increase in the cell and the cells become resistant to tyrosine kinase inhibitors. We suggest that Wnt antagonists carry the potential to be exploited in designing new agents and strategies for the advanced and resistant forms of chronic myeloid leukemia.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Drug Resistance, Neoplasm/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Repressor Proteins/genetics , beta Catenin/biosynthesis , Adaptor Proteins, Signal Transducing/biosynthesis , Ataxia Telangiectasia Mutated Proteins/biosynthesis , Ataxia Telangiectasia Mutated Proteins/genetics , Disease Progression , Fusion Proteins, bcr-abl/genetics , Hematopoietic Stem Cells/pathology , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Protein Kinase Inhibitors/administration & dosage , Repressor Proteins/biosynthesis , Wnt Signaling Pathway/drug effects , beta Catenin/genetics
3.
Turk J Haematol ; 29(4): 348-53, 2012 Dec.
Article in English | MEDLINE | ID: mdl-24385722

ABSTRACT

OBJECTIVE: At present, there are a limited number of facilities in Turkey that can provide reliable real-time quantitative(RQ)-PCR BCR-ABL results. The present study aimed to test a cost-effective, in-house method of BCR-ABL quantification,including verification of the method by RQ-PCR validation tests. MATERIAL AND METHODS: BCR-ABL and ABL target sequences were cloned into pJET1.2 vectors, from whichcalibrators were prepared and used as templates in RQ-PCR reactions to generate standard curves. Dilutions of K562cells (representing an in vitro simulation of BCR-ABL transcript reduction) were analyzed. RESULTS: Standard curves were generated from calibrators. These curves were then used to calculate the BCR-ABL andABL copy numbers; in which linear BCR-ABL results were obtained. Repetitive experiments showed that our methodologywas able to detect 1 BCR-ABL positive cell from amnong 1x105 cells. CONCLUSION: The method described herein is suitable for implementation with any RQ-PCR instrument and/or kit forquantify BCR-ABL transcripts. CONFLICT OF INTEREST: None declared.

4.
Leuk Res ; 34(7): 946-9, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20206998

ABSTRACT

Identifying gene expression differences in the Wnt signaling pathway specific to leukemic cells can be hampered by the lack of verified knowledge on the expression of WNT genes in normal blood cells. In this study we aimed to determine the expression profile of human WNT, FZD and sFRP genes in normal adult bone marrow, T and B cells; along with the hematopoietic cell lines K562, HL60, Jurkat and Namalwa. Bone marrow and peripheral blood from 16 donors were evaluated and our results were compared with the GeneNote database expression arrays. In bone marrow, only WNT3, WNT10A, FZD3, FZD7 and sFRP1 genes are constitutively expressed. Lymphocytes express WNT7A, WNT9B, FZD6 and FZD7 in addition to the genes above, but T cells differ in that they lose sFRP1 expression and gain constitutive expression of WNT16. An established "normal" profile of the Wnt genes in various blood cells will provide a fundamental basis for research investigating hematopoiesis and cellular processes during leukemic transformation.


Subject(s)
Bone Marrow Cells/metabolism , Frizzled Receptors/genetics , Gene Expression Profiling , Intercellular Signaling Peptides and Proteins/genetics , Lymphocyte Subsets/metabolism , Membrane Proteins/genetics , Wnt Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Cell Line, Tumor/metabolism , Child , Child, Preschool , Female , Frizzled Receptors/biosynthesis , HL-60 Cells/metabolism , Humans , Intercellular Signaling Peptides and Proteins/biosynthesis , Jurkat Cells/metabolism , K562 Cells/metabolism , Male , Membrane Proteins/biosynthesis , Middle Aged , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Wnt Proteins/biosynthesis , Young Adult
5.
Leuk Res ; 33(8): 1062-7, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19118898

ABSTRACT

Epigenetic silencing of sFRP genes has been shown to lead to constitutive activation of the canonical Wnt-signaling pathway. The first description of deregulated Wnt-signaling activation in a hematological malignancy was reported in chronic myeloid leukemia (CML). To investigate whether epigenetic silencing of sFRP is responsible for the observed Wnt activation in CML, we studied the methylation and mutational status of the sFRP1 promoter in 48 chronic phase CML patients. Of the 48 CML patients 41 were shown to be unmethylated, 6 patients hemi-methylated and 1 patient fully methylated at the sFRP1 promoter. Albeit observed infrequently in chronic phase CML, sFRP1 promoter methylation correlated with primary cytogenetic resistance to imatinib mesylate. sFRP1 promoter methylation may indicate a genetically more unstable form of disease resistant to therapy and provide a key biological difference in therapy resistant patients, in addition to a possible mechanism for the observed activation of canonical Wnt signaling in CML.


Subject(s)
DNA Methylation , Drug Resistance, Neoplasm , Intercellular Signaling Peptides and Proteins/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Membrane Proteins/metabolism , Philadelphia Chromosome , Promoter Regions, Genetic , Adolescent , Adult , Aged , Child , Female , Gene Silencing , Humans , Intercellular Signaling Peptides and Proteins/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Membrane Proteins/genetics , Middle Aged , Signal Transduction/genetics , Wnt Proteins/genetics , Wnt Proteins/metabolism
6.
Tumori ; 95(6): 836-9, 2009.
Article in English | MEDLINE | ID: mdl-20210255

ABSTRACT

AIMS AND BACKGROUND: Studies reporting activated Wnt signaling in all stages of chronic myeloid leukemia (CML) have demonstrated that deregulation of the pathway plays a role in the pathogenesis of this disease. Several reports have suggested mechanisms for the deregulated Wnt signaling and beta-catenin stabilization observed in CML. One possible mechanism for beta-catenin stabilization could be the acquisition of mutations at its N-terminal domain, especially in the third exon where it is marked via phosphorylation for degradation. We sought to determine whether mutations in the third exon of the beta-catenin gene are responsible for the observed Wnt activation in CML. MATERIAL AND METHODS: We screened bone marrow specimens from 33 patients with CML in the chronic phase and also examined the K562 cell line for beta-catenin mutations. RESULTS: None of the patients nor the K562 cell line were found to carry mutations. CONCLUSION: Beta-catenin amino-terminal mutations are not observed or very rare and therefore are not the underlying mechanism of activated Wnt signaling in CML.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mutation , Wnt Proteins/metabolism , beta Catenin/genetics , Bone Marrow/metabolism , Gene Expression Regulation, Neoplastic , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Phosphorylation , Polymerase Chain Reaction , Signal Transduction
7.
Oncol Rep ; 18(6): 1563-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17982645

ABSTRACT

With the aim of determining the differential expression of WNT and FZD genes, before and after induction of apoptosis in BCR-ABL positive cells, we treated the myeloid cell line K562 and control cell line HL60 with imatinib mesylate and etoposide, and analyzed relative mRNA expression levels of WNT, FZD and sFRP genes under normal and apoptotic conditions by real-time RT-PCR. We observed marked increase in mRNA levels of FZD4, FZD5, FZD7 and WNT5b, correlating with apoptotic activity and independent of the agent or cell line used. Our results suggest the involvement of non-canonical Wnt signaling in executing programmed cell death in myeloid cell lines.


Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , Leukemia, Myeloid/genetics , Leukemia, Promyelocytic, Acute/genetics , Wnt Proteins/genetics , Antineoplastic Agents/pharmacology , Benzamides , Caspase 3/genetics , Caspase 3/metabolism , Cell Line, Tumor , Cyclin D1/genetics , Etoposide/pharmacology , HL-60 Cells , Humans , Imatinib Mesylate , K562 Cells , Leukemia, Myeloid/pathology , Leukemia, Promyelocytic, Acute/pathology , Piperazines/pharmacology , Pyrimidines/pharmacology , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
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