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  • American Society of Hematology  (7)
  • Choi, Chan  (7)
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  • American Society of Hematology  (7)
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Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Denaturing- HPLC and HR-1 Melter-Based Detection of ABL Mutations in Patients with Chronic Myelogenous Leukemia (CML).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4876-4876
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4876-4876
    Abstract: Imatinib mesylate is the first line of drug for CML since its ability to induce durable remissions in most patients with Philadelphia-positive leukemias and cytogenetic responses in most patients with chronic-phase CML. Although Imatinib mesylate has revolutionized current chronic myeloid leukemia therapy the phenomenon of relapse because of the emergence of resistance were observed. There were well-known mutations in kinase domain that confer resistance despite continued Imatinib mesylate chemotherapy and number of resistance-conferring mutation is increasing. In this study we systematically scanned kinase domain-encoding exon 5, 7, 8, 9, 10 and 11 from genomic DNA of 79 patients with CML to identify novel mutation using denaturing high-performance liquid chromatography (dHPLC) and HR-1 melter (Idaho Technology). In total 15 mutations in the regions were identified and three mutations are found to be novel and two were located in the catalytic domain region (F359I and E374K). Since these two mutations were identified in patients with primary and secondary resistance respectively, it might be classified into resistance-conferring mutation conditional on further functional evaluation. Also we found P499L mutation in the C-terminus and interestingly we detected E478Q in six patients with CML. Analysis with dHPLC and HR-1 screening after PCR amplification proved to be accurate and effective methods to isolate mutation. In addition dHPLC and HR-1 more sensitive compared to PCR direct sequencing methods since two mutations which were not detected by direct sequencing were confirmed only after subcloning of PCR products and sequencing. Taken together, we designed six PCR amplicons encompassing the kinase domain of abl kinase and screened for novel mutations patients with CML. Out of fourteen mutations identified two novel mutations in the catalytic domain need further investigation to understand if they contribute to the acquirance of imatinib mesylate resistance
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.4876.4876
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    A Single Nucleotide Polymorphism and Its Haplotype of ZNF42 Transcriptional Modulator Gene Predisposes Individuals to High-Risk Acute Myelogenous Leukemia (AML).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4248-4248
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4248-4248
    Abstract: ZNF42 (MZF-1 or Human Zinc finger protein 42) is a hematopoietic transcription factor regulating the differentiation and proliferation of myeloid cells. ZNF42 belongs to the Krupple-class zinc finger protein, which is expressed in myeloid progenitor cells. As a transcriptional regulator it has been found to be pivotal in hematopoietic development, especially in granulopoiesis. ZNF42 is a bi-functional transcriptional regulator, by repressing transcription in non-hematopoietic cells, but trans-activating hematopoiesis-related genes. Despite the important role of ZNF42 in differentiation and proliferation in the myeloid lineage cells, molecular epidemiologic studies of ZNF42 have not been conducted. In this case-control study, we conducted a comprehensive analysis of the genomic region of ZNF42, including SNP discovery by re-sequencing of the promoter and exon-encompassing regions, haplotype construction and construction of linkage disequilibrium (LD) map and comparison LD structure among four different populations data from the International HapMap project. In total, 275 de novo AML patients plus age- and sex-matched controls were recruited and four coding non-synonymous SNPs were genotyped by Pyrosequencing for this study. All genotypes frequencies were in Hardy-Weinberg equilibrium. A non-synonymous SNP (G/A altering amino acid R51H) revealed strong association with increased susceptibility to AML. Relative to individuals with the GG genotype, those with the A allele (AA + AG) had a 4.8-fold (95% CI, 3.3–7.0) (p=4.111e-17) risk of development of AML. Also four common ( & gt; 5% frequency, cumulative frequency of over 96%) haplotypes were identified and the frequencies of the common haplotypes predicted were similar between cases and controls. When we studied if there is haplotype-based association to examine the contribution of common genetic variation at the ZNF42 locus to AML risk among Korean, two haplotypes (G-G and A-G from R51H-R130Q) showed statistically significant association.. These results suggest that ZNF42 variants and its haplotypes are significantly associated with increased susceptibility to AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.4248.4248
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Identification of Genes Associated with Risk to Aplastic Anemia (AA) Using Array-Based Genotyping.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4153-4153
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4153-4153
    Abstract: In this study we tested whether 3104 SNPs in 200 candidate genes were associated with risk to aplastic anemia (AA). Genes were considered potential candidates for their known or suspected roles in DNA repair system, pharmacogenomics and transcriptional regulation in hematopoiesis or putative pathways related to development of AA. Selection of SNPs was performed using dbSNP and HapMap project databases, with emphasis on non-synonymous SNPs or haplotype tagging SNPs. To discover potential SNPs responsible for AA susceptibility, a case-control study using Affymetrix targeted genotyping 3K array was designed. We applied 3K array to analyze the samples from 132 AA patients and 382 healthy controls. Genotyping were processed using GeneChip scanner 3000 TG(Affymetrix) and analyzed with GCOS software(Affymetrix). In total more than 160,000 SNPs were genotyped for this study. Samples with suboptimal call rates were excluded. Statistical testing were carried out using χ2, Cochran-Armitage trend, Fisher’s exact, odds ratio, haplotype estimation, LD block definition. Here we report that 19 SNPs in 14 genes are associated with elevated or reduced risk to AA. Three associated genes map to chromosome 11 and 16 respectively. Some of associated genes were transcription factors such as RARB and ZNF233. Among those associated SNPs, one was located in coding region while the rest of SNPs were located in introns of associated genes. In conclusion, we identified SNPs responsible for AA susceptibility by candidate gene-based SNP array approach. These promising data when supported by further molecular validation would greatly enhance the current understanding of AA predisposition and diseases progression. Implication of polymorphic variants in AA etiopathogenesis will be presented and discussed.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4153.4153
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Association of cis-Acting rs530 of the ETS2 Transcriptional Factor Gene with High-Risk Acute Myelogenous Leukemia (AML) and Allelic Expression Imbalance Assessment.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2230-2230
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2230-2230
    Abstract: We have previously implicated ETS2 in the etiopathogenesis of acute myeloid leukemia through case-control study by revealing that polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to acute myelogenous leukemia (AML). Two SNPs out of 7 genotyped sites, rs711 and rs530 were shown to be associated with increased risk to AML with the odds ratio (OR) of 1.76 (95% C.I. 1.2–2.5, p=0.0019) for rs711 and 1.67 (95% C.I. 1.3–2.2, p=0.0003) for rs530 relative to wild type genotypes respectively. Haplotype and linkage disequilibrium (LD) map was estimated, but haplotype association was not found with statistical significance. Korean LD structure was similar to Japanese LD, but least similarity was shown with LDs from African (Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants introduced in the sequence. Most dramatic change in the secondary structure was observed in the rs530 containing domain suggesting this variant of being cis-acting genetic variant. Real time Q-PCR and western blot analysis showed that expression of ETS2 decreased in individuals with heterozygous or mutant homozygous genotypes, showing most abundant expression with two wild type copies of rs530, less expression with the rare homozygous or heterozygous genotype. Sequencing cDNA of 55 heterozygous AML patients revealed mRNA expression imbalance in 13 cases (24%) effectively reverting heterozygous genotype to homozygous wild type mRNA species. The detection of a discrepancy between the mRNA alleles of rs530 clearly proves cis-acting effect of rs530. However there was not a case in 51 healthy control samples suggesting differing transcript levels derived from the two alleles of an autosomal gene is disease-specific phenomena. Taken together, our results suggest that two polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by inducing change in mRNA expression as a cis-acting variant.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2230.2230
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Two Single Nucleotide Polymorphisms of the ETS2 Transcriptional Factor Gene Predispose Individuals to High-Risk Acute Myelogenous Leukemia (AML).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2729-2729
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2729-2729
    Abstract: ETS2 (v-ets avian erythroblastosis virus E2 oncogene homolog 2) is a transcription factor located in the human chromosomal region 1q22.3 encoding a 56-kDa protein. In this study we carefully selected a set of haplotype-tagging SNPs (htSNP) and genotyped their frequencies in order to identify polymorphic variants that contributes to the inter-individual differences in susceptibility to disease phenotypes. Here we report polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to AML. Seven SNPs derived from genomic region of the ETS2 gene, rs1209953, rs3746882, rs2298560, rs457705, rs2070531, rs711 and rs5307 were genotyped to estimate allele frequency, haplotype block and linkage disequilibrium (LD) map. Among those rs711 and rs530 were shown to be associated with increased risk to AML with statistical significance. The odds ratio (OR) for rs711 and rs530 relative to wild type genotypes are 1.76 (95% C.I. 1.2–2.5, p=0.0019) and 1.67 (95% C.I. 1.3–2.2, p=0.0003) respectively. Cumulative frequencies of four common haplotypes are 72%, among which T-T-G-T-C-G-T was the most ancestral haplotype comprising 36% of total haplotypes. We also examined the possibility of haplotype association, but no association was found. When we compared LD map with LDs constructed from the International HapMap project, Korean LD map was similar to Japanese LD, but least similarity was shown with LDs from African(Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants sequence. Severe change in the secondary structure was observed in the rs530 containing domain suggesting this change might affects stability of mRNA. Real time Q-PCR and western blot revealed that expression of ETS2 decreased in a dosage-dependant manner, showing most abundant expression when homozygously T/T at rs530, least expression with the homozygous A/A and intermediate level of expression when the heterozygous genotype. Our results suggest that polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by altering the secondary structure of mRNA.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2729.2729
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Case-Control Study Using Array-Based Genotyping Produced a Panel of Genes Associated with Risk to Acute Myelogenous Leukemia (AML).
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2384-2384
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2384-2384
    Abstract: Multiple loci with small genetic effects are thought to be linked to AML pathogenesis. To detect such loci requires systematic screening of large number of single nucleotide polymorphisms (SNPs) within large study population. In this study we tested whether 3104 SNPs in 200 candidate genes were associated with risk to AML. Genes were considered potential candidates for their known or suspected roles in DNA repair system, pharmacogenomics and transcriptional regulation in hematopoiesis or putative pathways related to leukemogenesis. Selection of SNPs was performed using dbSNP and HapMap project databases, with emphasis on non-synonymous SNPs or haplotype tagging SNPs. To discover potential SNPs responsible for AML susceptibility, we conducted a case-control study using Affymetrix targeted genotyping 3K array. We applied this platform to analyze the samples from 309 de novo AML patients and 382 healthy controls. Genotype scorings were processed using GeneChip scanner 3000 TG(Affymetrix) and analyzed with GCOS software(Affymetrix). In total more than 255,000 SNPs were genotyped for this study. Samples with suboptimal call rates were excluded. Statistical testing were carried out using χ2, Cochran-Armitage trend, Fisher’s exact, odds ratio, haplotype estimation, LD block definition. Here we report that 23 SNPs in 16 genes are associated with elevated or reduced risk to AML. Some of associated genes were transcription factors such as ZNF23 and ZNF233. While associated genes were distributed evenly among the whole genome, four associated genes were found on chromosome 1. Among those associated SNPs, two were located in coding region, one in exon-intron boundary, while the rest of SNPs were located in introns of associated genes. Among 23 SNPs identified, two intronic SNPs from 1st intron of BAALC(Brain and acute leukemia, cytoplasmic) gene were associated with the reduced risk to AML. Haplotype estimation and linkage disequilibrium pattern of 9 SNPs including two associated SNPs will be presented. In conclusion, we identified SNPs responsible for AML susceptibility by candidate gene-based SNP array approach. These promising data when supported by further molecular validation would greatly enhance the current understanding of AML predisposition and diseases progression. Implication of polymorphic variants in AML etiopathogenesis will be presented and discussed.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2384.2384
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    High-Sensitivity Mutational Analysis of BCR-ABL Mutations in the Kinase Domain Using Pyrosequencing Could Provides Alternative Methodology for Monitoring the Proportion of Mutant Alleles in Patient with Chronic Myelogenous Leukemia.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4801-4801
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4801-4801
    Abstract: Imatinib mesylate has substantially changed treatment of chronic myeloid leukemia (CML). But the resistance-conferring mutations in tyrosine KD (Kinase Domain) of BCR-ABL region constitute the leading cause of clinical resistance in CML patients on imatinib or dasatinib monotheray. Therefore early detection and accurate quantification of the common mutations in KD in post-transplantation patient could provide vital information regarding disease progression or prognosis. Here we report results of pyrosequencing to quantify the non-mutated and mutant alleles in 11 CML patients who were treated by imatinib mesylate or dasatinib. Patients were monitored over periods ranging from 24 to 67 months. 11 mutations in the region identified by direct or pyrosequencing and/or pGEMT cloning are Y215F, T253F, E255K, L323P, N336S, A337T, M351T, E355K, F359I, H396R and P480L. Out of 11 mutations, two (F359I and P480L) are found to be novel. Four mutations (L323P, N336S, A337T and E355K) were positioned between P loop and catalytic domain, one (F359I) was in the activation domain and one (P480L) was near to the carboxy terminal of the kinase. One novel mutation (Y215F) located outside (N terminal region of kinase domain) region was also identified. Y215F mutation which lies outside the kinase domain might be sporadic one without affecting kinase activity. We successfully measured proportion of KD mutant cells with greater precision by using pyrosequencing (Fig 1). The dynamics of the mutated clones obtained from pyrosequencing were correlated with RQ-PCR (Fig2) suggesting quantitative pyrosequencing method could be alternative to various methods including allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) and conventional sequencing which have limited sensitivity at low concentrations of mutant allele. Taken together, we established a novel method for early identification of KD mutations and precise monitoring of the proportion of mutant alleles in patient with CML. Most importantly, those results were in correlation with clinical response to imatinib mesylate or dasatinib. Therefore quantitative measurement of mutant cell dynamics could provide early indications of clinically significant disease progression. T3151 mutation T3151 mutation T3151 Mutation T3151 Mutation
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4801.4801
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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