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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


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.


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.


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.


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.

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