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Kim J.-H.,Sogang University | Lee C.,Seoul National University | Cheong H.S.,Seoul National University | Cheong H.S.,SNP Genetics Inc. | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2016

Purpose: The solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1) is known to be involved in the transportation and resistance of the nucleoside analog cytosine arabinoside (AraC), one of the most effective drugs in the treatment of acute myeloid leukemia (AML). Methods: In vitro functional analysis in AML cells and genetic association study were performed. Results: Our functional analysis of SLC29A1 on anticancer effects of AraC showed that cytotoxic effects of AraC in AML cell lines were decreased by the reduction of SLC29A1 expression (P < 0.05). To investigate whether SLC29A1 polymorphisms could affect the achievement of complete remission (CR) in AML, we genotyped a total of six common single nucleotide polymorphisms on SLC29A1 in 103 AML patients, including 17 successes and 86 failures in CR. As a result, rs3734703 in 3’-untranslated region was significantly associated with CR even after correction for multiple testing (Fisher’s exact test, P = 0.008; Pcorr = 0.04). A haplotype, ht3 (A–G–G–T–C–A; frequency = 0.294 in success group; frequency = 0.120 in failure group), also revealed a significant association with CR (P = 0.01; simulated Psim = 0.02). Conclusions: Although further replication in larger subjects and further functional evaluations are required, our results suggest the contribution of SLC29A1 to cytotoxic effects of AraC. In addition, genetic variations of SLC29A1 could be a potential marker for the achievement of CR of cancers of white blood cells including AML. © 2016 Springer-Verlag Berlin Heidelberg


Cheong H.S.,Seoul National University | Cheong H.S.,SNP Genetics Inc. | Koh Y.,Seoul National University | Ahn K.-S.,PDXen Biosystem Inc. | And 4 more authors.
Pharmacogenetics and Genomics | Year: 2014

AIMS: The cytosolic 5′-nucleotidase-III (NT5C3) is involved in the metabolism of the nucleoside analog, cytosine arabinose (AraC), and the expression level of NT5C3 is correlated with sensitivity to AraC in acute myeloid leukemia (AML) patients. The current study examined whether the NT5C3 polymorphisms could affect chemotherapy outcomes in 103 Korean AML patients. METHODS: Forty-seven single nucleotide polymorphisms in NT5C3 were genotyped using the Illumina GoldenGate genotyping assay. The genetic effects of the polymorphisms on the outcome of chemotherapy were analyzed using χ and logistic regression models. RESULTS: Although none of the NT5C3 polymorphisms was associated with a complete remission rate, a common single nucleotide polymorphism, rs3750117, showed a significant association with induction rate after the first course of chemotherapy (Pcorr=0.004 and odds ratio=11.28) in AML patients. In addition, NT5C3 expression levels were significantly increased in patients with risk allele homozygote. CONCLUSIONS: The data suggest that genotyping the NT5C3 polymorphism may have the potential to identify patients more likely to respond to AraC-based chemotherapy. Copyright © Lippincott Williams & Wilkins.


PubMed | Sogang University, PDXen Biosystem Inc., Korea Basic Science Institute and Seoul National University
Type: | Journal: Annals of hematology | Year: 2016

The minichromosome maintenance complex component 7 (MCM7) encodes a member of MCM complex, which plays a critical role in the initiation of gene replication. Due to the importance of MCM complex, MCM7 gene has been regarded as a candidate gene for cancer development. In the present study, seven MCM7 polymorphisms were genotyped in 344 subjects composed of 103 acute myeloid leukemia (AML) patients and 241 normal controls to examine the possible associations between MCM7 polymorphisms and the risk of AML. MCM7 polymorphisms were not associated with the risk of AML (P>0.05). However, MCM7 polymorphisms were significantly related to the relapse of AML and overall survival. The rs2070215 (N144S) showed a protective effect to the risk of AML relapse (OR=0.37; P


PubMed | Ewha Womans University, Sogang University, PDXen Biosystem Inc. and Seoul National University
Type: Journal Article | Journal: Cancer chemotherapy and pharmacology | Year: 2016

The solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1) is known to be involved in the transportation and resistance of the nucleoside analog cytosine arabinoside (AraC), one of the most effective drugs in the treatment of acute myeloid leukemia (AML).In vitro functional analysis in AML cells and genetic association study were performed.Our functional analysis of SLC29A1 on anticancer effects of AraC showed that cytotoxic effects of AraC in AML cell lines were decreased by the reduction of SLC29A1 expression (P<0.05). To investigate whether SLC29A1 polymorphisms could affect the achievement of complete remission (CR) in AML, we genotyped a total of six common single nucleotide polymorphisms on SLC29A1 in 103 AML patients, including 17 successes and 86 failures in CR. As a result, rs3734703 in 3-untranslated region was significantly associated with CR even after correction for multiple testing (Fishers exact test, P=0.008; P corr=0.04). A haplotype, ht3 (A-G-G-T-C-A; frequency=0.294 in success group; frequency=0.120 in failure group), also revealed a significant association with CR (P=0.01; simulated P sim=0.02).Although further replication in larger subjects and further functional evaluations are required, our results suggest the contribution of SLC29A1 to cytotoxic effects of AraC. In addition, genetic variations of SLC29A1 could be a potential marker for the achievement of CR of cancers of white blood cells including AML.


PubMed | Sogang University, PDXen Biosystem Inc. and Seoul National University
Type: Journal Article | Journal: Genetic testing and molecular biomarkers | Year: 2016

Some members of the poly ADP-ribose polymerase (PARP) protein family have been regarded as targets for the therapeutic inhibition of cancer. Among these PARP genes, poly ADP-ribose polymerase family, member 15 (PARP15) is a candidate gene for cancer development due to its ability to regulate gene transcription and its reported association with apoptosis. The current study investigated the possible association between PARP15 single-nucleotide polymorphisms and the risk of acute myeloid leukemia (AML). In addition, we analyzed the effects of the PARP15 polymorphisms on the clinical phenotypes associated with cytosine arabinose (AraC) chemotherapy in AML patients.Ten PARP15 polymorphisms were genotyped via TaqMan assay in a total of 344 Korean subjects, including 103 AML patients and 241 normal controls. The genetic effects of the polymorphisms on the risk of AML and the clinical phenotypes were analyzed using Statistical Analysis System (SAS) software.The results from a Cox regression analysis for overall survival revealed that two polymorphisms were associated with increased overall survival and the signal for rs17208928 was retained after correcting for multiple tests (pThese results suggest the possibility that the PARP15 gene may be a potential therapeutic target in AML patients although much larger scale studies are needed for validation.


Park J.,Seoul National University | Bae E.-K.,PDxen Biosystem Inc. | Lee C.,Seoul National University | Choi J.-H.,Seoul National University | And 3 more authors.
BMB Reports | Year: 2014

Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/ velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients. © 2014 by the The Korean Society for Biochemistry and Molecular Biology.


Koh Y.,Seoul National University | Jung W.-J.,Seoul National University | Ahn K.-S.,Seoul National University | Ahn K.-S.,PDXen Biosystem Inc. | Yoon S.-S.,Seoul National University
BioMed Research International | Year: 2014

Purpose. We tried to establish clinically relevant human myeloma cell lines that can contribute to the understanding of multiple myeloma (MM). Materials and Methods. Mononuclear cells obtained from MM patient's bone marrow were injected via tail vein in an NRG/SCID mouse. Fourteen weeks after the injection, tumor developed at subcutis of the mouse. The engraftment of MM cells into mouse bone marrow (BM) was also observed. We separated and cultured cells from subcutis and BM. Results. After the separation and culture of cells from subcutis and BM, we established two cell lines originating from a single patient (SNU-MM1393-BM and SNU-MM1393-SC). Karyotype of the two newly established MM cell lines showed tetraploidy which is different from the karyotype of the patient (diploidy) indicating clonal evolution. In contrast to SNU-MM1393-BM, cell proliferation of SNU-MM1393-SC was IL-6 independent. SNU-MM1393-BM and SNU-MM1393-SC showed high degree of resistance against bortezomib compared to U266 cell line. SNU-MM1393-BM had the greater lethality compared to SNU-MM1393-SC. Conclusion. Two cell lines harboring different site tropisms established from a single patient showed differences in cytokine response and lethality. Our newly established cell lines could be used as a tool to understand the biology of multiple myeloma. © 2014 Youngil Koh et al.


Koh Y.,Seoul National University | Kim D.,Seoul National University | Jung W.-J.,Seoul National University | Ahn K.-S.,PDXen Biosystem Inc. | Yoon S.-S.,Seoul National University
International Journal of Genomics | Year: 2015

Background. Previously we established two cell lines (SNU-MM1393-BM and SNU-MM1393-SC) from different tissues (bone marrow and subcutis) of mice which were injected with single patient's myeloma sample. We tried to define genetic changes specific for each cell line using whole exome sequencing (WES). Materials and Methods. We extracted DNA from SNU-MM1393-BM and SNU-MM1393-SC and performed WES. For single nucleotide variants (SNV) calling, we used Varscan2. Annotation of mutation was performed using ANNOVAR. Results. When calling of somatic mutations was performed, 68 genes were nonsynonymously mutated only in SNU-MM1393-SC, while 136 genes were nonsynonymously mutated only in SNU-MM1393-BM. KIAA1199, FRY, AP3B2, and OPTC were representative genes specifically mutated in SNU-MM1393-SC. When comparison analysis was performed using TCGA data, mutational pattern of SNU-MM1393-SC resembled that of melanoma mostly. Pathway analysis using KEGG database showed that mutated genes specific of SNU-MM1393-BM were related to differentiation, while those of SNU-MM1393-SC were related to tumorigenesis. Conclusion. We found out genetic changes that underlie tropism of myeloma cells using WES. Genetic signature of cutaneous plasmacytoma shares that of melanoma implying common mechanism for skin tropism. KIAA1199, FRY, AP3B2, and OPTC are candidate genes for skin tropism of cancers. © 2015 Youngil Koh et al.


PubMed | PDXen Biosystem Inc. and Seoul National University
Type: | Journal: International journal of genomics | Year: 2015

Background. Previously we established two cell lines (SNU_MM1393_BM and SNU_MM1393_SC) from different tissues (bone marrow and subcutis) of mice which were injected with single patients myeloma sample. We tried to define genetic changes specific for each cell line using whole exome sequencing (WES). Materials and Methods. We extracted DNA from SNU_MM1393_BM and SNU_MM1393_SC and performed WES. For single nucleotide variants (SNV) calling, we used Varscan2. Annotation of mutation was performed using ANNOVAR. Results. When calling of somatic mutations was performed, 68 genes were nonsynonymously mutated only in SNU_MM1393_SC, while 136 genes were nonsynonymously mutated only in SNU_MM1393_BM. KIAA1199, FRY, AP3B2, and OPTC were representative genes specifically mutated in SNU_MM1393_SC. When comparison analysis was performed using TCGA data, mutational pattern of SNU_MM1393_SC resembled that of melanoma mostly. Pathway analysis using KEGG database showed that mutated genes specific of SNU_MM1393_BM were related to differentiation, while those of SNU_MM1393_SC were related to tumorigenesis. Conclusion. We found out genetic changes that underlie tropism of myeloma cells using WES. Genetic signature of cutaneous plasmacytoma shares that of melanoma implying common mechanism for skin tropism. KIAA1199, FRY, AP3B2, and OPTC are candidate genes for skin tropism of cancers.

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