45 results on '"Eun-Hye Hur"'
Search Results
2. Antileukemic activity of YPN-005, a CDK7 inhibitor, inducing apoptosis through c-MYC and FLT3 suppression in acute myeloid leukemia
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Bon-Kwan Koo, Eun-Ji Choi, Eun-Hye Hur, Ju Hyun Moon, Ji Yun Kim, Han-Seung Park, Yunsuk Choi, Jung-Hee Lee, Kyoo-Hyung Lee, Eun Kyung Choi, Jinhwan Kim, and Je-Hwan Lee
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Acute myeloid leukemia (AML) ,Cyclin dependent kinase 7 (CDK7) inhibitor ,c-MYC ,MCL1 ,FLT3 ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer with a high rate of relapse associated with adverse survival outcomes, especially in elderly patients. An aberrant expression of cyclin dependent kinase 7 (CDK7) is associated with poor outcomes and CDK7 inhibition has showed antitumor activities in various cancers. We investigated the efficacy of YPN-005, a CDK7 inhibitor in AML cell lines, xenograft mouse model, and primary AML cells. YPN-005 effectively inhibited the proliferation of AML cells by inducing apoptosis and reducing phosphorylation of RNA polymerase II. The c-MYC expression decreased with treatment of YPN-005, and the effect of YPN-005 was negatively correlated with c-MYC expression. YPN-005 also showed antileukemic activities in primary AML cells, especially those harboring FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) mutation and in in vivo mouse model. Phosphorylated FLT3/Signal transducer and activator of transcription 5 (STAT5) was decreased and FLT3/STAT5 was downregulated with YPN-005 treatment. Our data suggest that YPN-005 has a role in treating AML by suppressing c-MYC and FLT3.
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- 2022
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3. Expression and prognostic significance of microRNAs in Korean patients with myelodysplastic syndrome
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Yunsuk Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Dae Ro Choi, and Je-Hwan Lee
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myelodysplastic syndromes ,mirn126 microrna, human ,hsa-146b-5p ,mirn155 microrna, human ,mirn200 microrna, human ,Medicine - Abstract
Background/Aims Various alterations of microRNA (miRNA) expression have been reported in myelodysplastic syndrome (MDS). We aimed to investigate the unique patterns and prognostic significance of miRNA expression in Korean patients with MDS. Methods Bone marrow mononuclear cells were collected from eight healthy controls and 26 patients with MDS, and miRNAs were isolated and assessed via quantitative real-time polymerase chain reaction for selected miRNAs, including miR-21, miR-124a, miR-126, miR-146b-5p, miR-155, miR-182, miR-200c, miR-342-5p, miR-708, and Let-7a. Results MiR-124a, miR-155, miR-182, miR-200c, miR-342-5p, and Let-7a were significantly underexpressed in patients with MDS, compared to healthy controls. MiR-21, miR-126, 146b-5p, and miR-155 transcript levels were significantly lower in international prognostic scoring system lower (low and intermediate-1) risk MDS than in higher (intermediate-2 and high) risk MDS. Higher expression levels of miR-126 and miR-155 correlated with significantly shorter overall survival and leukemia-free survival. Higher miR-124a expression also tended to be related to shorter survivals. Conclusions Although our study was limited by the relatively small number of patients included, we identified several miRNAs associated with pathogenesis, leukemic transformation, and prognosis in MDS.
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- 2019
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4. Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia
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Eun-Ji Choi, Young-Uk Cho, Eun-Hye Hur, Seongsoo Jang, Nayoung Kim, Han-Seung Park, Jung-Hee Lee, Kyoo-Hyung Lee, Si-Hwan Kim, Sang-Hyun Hwang, Eul-Ju Seo, Chan-Jeoung Park, and Je-Hwan Lee
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.
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- 2021
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5. Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells
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Eun-Ji, Choi, Bon-Kwan, Koo, Eun-Hye, Hur, Ju Hyun, Moon, Ji Yun, Kim, Han-Seung, Park, Yunsuk, Choi, Kyoo-Hyung, Lee, Jung-Hee, Lee, Eun Kyung, Choi, and Je-Hwan, Lee
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Pharmacology ,Drug Discovery ,Molecular Medicine ,Biochemistry - Abstract
Resistance to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a concerning problem. Polo-like kinase 1 (PLK1) is a key cell cycle modulator and is known to be associated with an activation of the PI3K pathway, which is related to the stabilization of DNA methyltransferase 1 (DNMT1), a target of HMAs. We investigated the effects of volasertib on HMA-resistant cell lines (MOLM/AZA-1 and MOLM/DEC-5) derived from MOLM-13, and bone marrow (BM) samples obtained from patients with MDS (BM blasts5%) or AML evolved from MDS (MDS/AML). Volasertib effectively inhibited the proliferation of HMA-resistant cells with suppression of DNMTs and PI3K/AKT/mTOR and ERK pathways. Volasertib also showed significant inhibitory effects against primary BM cells from patients with MDS or MDS/AML, and the effects of volasertib inversely correlated with
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- 2022
6. Why are they leaving? Understanding Associations between early childhood program policies and teacher turnover rates
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Eun Hye Hur, Katherine Ardeleanu, Tonya W. Satchell, and Lieny Jeon
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Life-span and Life-course Studies ,Social Sciences (miscellaneous) - Published
- 2022
7. Clinical implications and genetic features of clonal cytopenia of undetermined significance compared to lower-risk myelodysplastic syndrome
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Eun‐Ji Choi, Young‐Uk Cho, Eun‐Hye Hur, Han‐Seung Park, Yunsuk Choi, Jung‐Hee Lee, Kyoo‐Hyung Lee, Miyoung Kim, Sang‐Hyun Hwang, Seongsoo Jang, Chan‐Jeoung Park, Eul‐Ju Seo, and Je‐Hwan Lee
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Chromosome Aberrations ,Hemoglobins ,Myelodysplastic Syndromes ,Mutation ,Humans ,Hematology ,Clonal Hematopoiesis - Abstract
Clonal cytopenia of undetermined significance (CCUS) is characterized by persistent cytopenias with genetic aberrations, which do not meet the diagnostic criteria for myelodysplastic syndrome (MDS). We aimed to compare the clinical and genetic characteristics of CCUS with lower-risk MDS and identify patients with CCUS with a high risk of progression. We performed targeted sequencing of bone marrow (BM) samples from patients with idiopathic cytopenia of undetermined significance (ICUS) (n = 139) and MDS (n = 226). Overall survival (OS) of patients with CCUS (n = 78) was worse than non-clonal ICUS (n = 61) and superior to lower-risk MDS (n = 99). Patients with CCUS showed similar characteristics to those with lower-risk MDS, except for higher haemoglobin, lower BM cellularity, and less frequent SF3B1 mutations. Lower haemoglobin, DDX41 (biallelic germline and somatic), ETV6, and RUNX1 mutations were independent prognostic factors for worse OS. Lower haemoglobin and DDX41 mutations were also associated with lower progression-free survival. Patients with CCUS with high-risk features showed similar or worse OS than patients with lower-risk MDS. Our findings suggest that patients with CCUS having certain clinical or genetic features should be regarded and treated as lower-risk MDS despite lacking significant dysplasia or MDS-associated chromosomal abnormalities.
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- 2022
8. Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia
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Je-Hwan Lee, Seongsoo Jang, Sihwan Kim, Young-Uk Cho, Kyoo-Hyung Lee, Jung-Hee Lee, Sang-Hyun Hwang, Chan-Jeoung Park, Eun-Ji Choi, Han-Seung Park, Eul-Ju Seo, Eun-Hye Hur, and Nayoung Kim
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Oncology ,0303 health sciences ,Mutation ,medicine.medical_specialty ,Cytopenia ,Myeloid ,business.industry ,Incidence (epidemiology) ,Myeloid leukemia ,Karyotype ,Hematology ,medicine.disease_cause ,medicine.disease ,Germline ,Myeloid Neoplasm ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,030304 developmental biology - Abstract
DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.
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- 2021
9. Creating an educational context for Open Source Intelligence: The development of Internet self-efficacy through a blogcentric course.
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Yunhwan Kim, Michael Glassman, Mitchell Bartholomew, and Eun Hye Hur
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- 2013
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10. Adverse childhood experiences, and instability in Children's care and Parents' work
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Rachel Eun Hye Hur, Adrienne J. L. Henry, Emiko Goka-Dubose, and Shannon T. Lipscomb
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Sociology and Political Science ,media_common.quotation_subject ,05 social sciences ,050301 education ,Fragile Families and Child Wellbeing Study ,Mental illness ,medicine.disease ,Education ,Developmental psychology ,Neglect ,Substance abuse ,Work (electrical) ,Developmental and Educational Psychology ,medicine ,0501 psychology and cognitive sciences ,Early childhood ,Adverse Childhood Experiences ,Psychology ,0503 education ,050104 developmental & child psychology ,media_common - Abstract
Adverse Childhood Experiences (ACEs), such as abuse, neglect, exposure to violence, parental mental illness and substance abuse are linked with a host of negative life outcomes. To support young children facing ACEs through Early Care and Education (ECE), challenges such as instability must be understood and addressed. This study examines associations between ACEs during early childhood and instability related to ECE among 2, 466 children attending ECE in the Fragile Families and Child Wellbeing Study. Parents reported instability in children's ECE and disruptions in their work or school stemming from instability in children's ECE. Parents also reported indicators of ACEs when children were three years of age. Over half of the children had at least one ACE; 12% had three or more. Children's ACEs predicted more instability, in both children's ECE, and in disruptions in parents' work/school due to problems arranging and keeping ECE.
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- 2019
11. Unique ethnic features of
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Eun-Ji, Choi, Young-Uk, Cho, Eun-Hye, Hur, Seongsoo, Jang, Nayoung, Kim, Han-Seung, Park, Jung-Hee, Lee, Kyoo-Hyung, Lee, Si-Hwan, Kim, Sang-Hyun, Hwang, Eul-Ju, Seo, Chan-Jeoung, Park, and Je-Hwan, Lee
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DEAD-box RNA Helicases ,Male ,Leukemia, Myeloid, Acute ,Myeloproliferative Disorders ,Myelodysplastic Syndromes ,Mutation ,Ethnicity ,Humans ,Hematologic Diseases - Abstract
DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.
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- 2020
12. Comparison of anthracyclines used for induction chemotherapy in patients with FLT3 -ITD-mutated acute myeloid leukemia
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Miee Seol, Juhyun Moon, Eun-Hye Hur, Young-Shin Lee, Kyoo-Hyung Lee, Eun-Ji Choi, Jung-Hee Lee, Han-Seung Park, Je-Hwan Lee, Yeon Hee Kim, Young-Ah Kang, Mijin Jeon, Ji Min Woo, Bon-Kwan Goo, and Sun-Hye Ko
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Anthracycline ,Daunorubicin ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Idarubicin ,Aged ,Retrospective Studies ,Antibiotics, Antineoplastic ,Dose-Response Relationship, Drug ,business.industry ,Remission Induction ,Induction chemotherapy ,Myeloid leukemia ,Induction Chemotherapy ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Leukemia, Myeloid, Acute ,Leukemia ,Regimen ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Mutation ,Cytarabine ,Female ,business ,medicine.drug - Abstract
This retrospective analysis compared anthracyclines (as part of an induction regimen) in 128 newly diagnosed FLT3-ITD-mutated AML patients. Induction regimens comprised high-dose daunorubicin (HD-DN; 90 mg/m2/d × 3d; n = 44), standard-dose daunorubicin (SD-DN; 45 mg/m2/d × 3d; n = 51), or idarubicin (IDA; 12 mg/m2/d × 3d; n = 33) in combination with cytarabine (100–200 mg/m2/d × 7d). Fifty-three patients showing persistent leukemia on interim bone marrow examination received a second course of induction chemotherapy comprising 2 days of daunorubicin (45 mg/m2/d) or IDA (8 or 12 mg/m2/d) in addition to 5 days of cytarabine. Complete remission (CR) rates were 77.3%, 56.9%, and 69.7% for HD-DN, SD-DN, and IDA, respectively (P = 0.101; HD-DN vs. SD-DN, P = 0.036; HD-DN vs. IDA, P = 0.453; IDA vs. SD-DN, P = 0.237). The HD-DN showed higher overall survival (OS) and event-free survival (EFS) than SD-DN and IDA: the differences between HD-DN and SD-DN (P = 0.009 for OS and P = 0.010 for EFS) were statistically significant. Results of in vitro studies using FLT3-ITD-mutated cell lines supported these findings. In conclusion, HD-DN improved the CR rate, OS, and EFS of FLT3-ITD-mutated AML patients. HD-DN also tended to yield better outcomes than IDA, though the difference was not significant. The superiority of HD-DN over IDA should be confirmed in future studies.
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- 2018
13. Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia
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Hun Mo Ryoo, Yunsuk Choi, Won-Sik Lee, Eun-Hye Hur, Gyeong Won Lee, Myung Soo Hyun, Jung Lim Lee, Jihyun Kwon, Hyo Jung Kim, Sang Min Lee, Sung-Nam Lim, Je-Hwan Lee, Kyoo-Hyung Lee, Young-Don Joo, Jung-Hee Lee, Hawk Kim, Dae Young Zang, Dae-Young Kim, Sung Hwa Bae, and Min Kyoung Kim
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Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Daunorubicin ,Pharmacology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Idarubicin ,Cumulative incidence ,Prospective Studies ,Survival rate ,Dose-Response Relationship, Drug ,business.industry ,Cytarabine ,Induction chemotherapy ,Myeloid leukemia ,Induction Chemotherapy ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Purpose We compared two induction regimens, idarubicin (12 mg/m2/d for 3 days) versus high-dose daunorubicin (90 mg/m2/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2/d for 7 days). Results Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event-free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028). Conclusion This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.
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- 2017
14. Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells
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Juhyun Moon, Gilnam Lee, Suk Young Cho, Yunsuk Choi, Jene Choi, Choung-Soo Kim, Sang-Hwa Yang, Kyun-Seop Bae, Jeongbeob Seo, Je-Hwan Lee, Bon-Kwan Goo, Jung Jin Hwang, and Eun-Hye Hur
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0301 basic medicine ,MAPK/ERK pathway ,Cell Survival ,HL-60 Cells ,resistance ,03 medical and health sciences ,0302 clinical medicine ,Transcription Factor 4 ,Cell Line, Tumor ,melanoma ,Medicine ,Gene silencing ,Humans ,Transcription factor ,Protein Kinase Inhibitors ,Wnt Signaling Pathway ,Mitogen-Activated Protein Kinase Kinases ,Oncogene ,business.industry ,MEK inhibitor ,Gene Expression Profiling ,Wnt signaling pathway ,beta-catenin ,TCF4 ,MAPK ,ITF-2 ,3. Good health ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Benzimidazoles ,RNA Interference ,business ,K562 Cells ,Research Paper - Abstract
Primary or acquired resistance to MEK inhibitors has been a barrier to successful treatment with MEK inhibitors in many tumors. In this study, we analyzed genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines to identify candidate genes whose expression changes are associated with responses to a MEK inhibitor, selumetinib (AZD6244). Of 62 identified differentially expressed genes, we selected Immunoglobulin Transcription Factor 2, also known as transcription factor 4 as a potential drug resistance marker for further analysis. This was because the ITF-2 expression increase in resistant cell lines was relatively high and a previous study has suggested that ITF-2 functions as an oncogene in human colon cancers. We also established an AZD6244 resistant cell line (M14/AZD-3) from an AZD6244 sensitive M14 cell line. The expression of the ITF-2 was elevated both in primary AZD6244 resistant cell line, LOX-IMVI and acquired resistant cell line, M14/AZD-3. Targeted silencing of ITF-2 by siRNA significantly enhanced susceptibility to AZD6244 in resistant cells. Wnt/β-catenin pathway was activated through direct interaction of p-ERK and GSK3β. Our results suggest that up-regulation of the ITF-2 gene expression is associated with cellular resistance to MEK inhibitors, and activation of Wnt signaling pathway through interaction of p-ERK and GSK3β seems to be a mechanism for increase of ITF-2.
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- 2017
15. Establishment and characterization of hypomethylating agent-resistant cell lines, MOLM/AZA-1 and MOLM/DEC-5
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Je-Hwan Lee, Bon-Kwan Goo, Yunsuk Choi, Dae Ro Choi, Seung-Hyun Jung, Yeun-Jun Chung, Eun-Hye Hur, and Juhyun Moon
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0301 basic medicine ,Gerontology ,Oncology ,azacitidine ,medicine.medical_specialty ,Azacitidine ,Decitabine ,Single-nucleotide polymorphism ,cytogenetics ,MOLM-13 ,resistance ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Hematology ,business.industry ,Cytogenetics ,Myeloid leukemia ,DNA Methylation ,Prognosis ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Hypomethylating agent ,030220 oncology & carcinogenesis ,business ,Research Paper ,medicine.drug ,Comparative genomic hybridization - Abstract
// Eun-Hye Hur 1, * , Seung-Hyun Jung 2, 3, * , Bon-Kwan Goo 1 , Juhyun Moon 1 , Yunsuk Choi 4 , Dae Ro Choi 5 , Yeun-Jun Chung 3, 6 , Je-Hwan Lee 1 1 Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea 3 Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea 4 Division of Hematology and Hematological Malignancies, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea 5 Division of Hemato-Oncology, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea 6 Department of Microbiology, College of Medicine, The Catholic University of Korea * These authors have contributed equally to this work Correspondence to: Je-Hwan Lee, email: jhlee3@amc.seoul.kr Yeun-Jun Chung, email: yejun@catholic.ac.kr Keywords: azacitidine, decitabine, MOLM-13, resistance, cytogenetics Received: June 16, 2016 Accepted: December 05, 2016 Published: December 28, 2016 ABSTRACT Two hypomethylating agents (HMAs), azacitidine and decitabine, have demonstrated clinical activities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, potential problems include development of acquired resistance. HMA-resistant patients have very poor prognosis and this cohort of patients constitutes an important area of research. To understand the mechanisms underlying HMA-resistance and to overcome it, we established an azacitidine-resistant cell line, MOLM/AZA-1 and a decitabine-resistant cell line, MOLM/DEC-5 using MOLM-13. For cytogenetic characterization, we performed microarray-based comparative genomic hybridization (array-CGH), which identified a total of 15 copy number alterations (CNAs). Among these CNAs, eight regions in HMA-resistant cell lines showed CNA patterns distinct from the parental MOLM-13 genome. Single nucleotide polymorphism (SNP) microarray was also performed to obtain a more reliable interpretation of the identified CNAs, and all HMA-resistance-specific CNAs except one detected by array-CGH were successfully validated. In addition to CNAs, copy neutral loss of heterozygosity and mosaic loss events were identified in HMA-resistant cell lines. In our resistant cell lines, MDR-1 was not overexpressed, while DNMT3b was upregulated. Azacitidine and decitabine did not inhibit DNMT1, DNMT3a, or DNMT3b in both HMA-resistant cell lines, while they inhibited the enzymes in parental MOLM-13. We also developed mouse xenograft models using MOLM/AZA-1 and MOLM/DEC-5. Our in vitro and in vivo models of HMA-resistant cell lines will provide clues for the elucidation of molecular mechanisms related to the development of resistance to HMA and tools for the application of novel therapeutics for AML and MDS.
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- 2016
16. Clinical implications of copy number alteration detection using panel-based next-generation sequencing data in myelodysplastic syndrome
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Hye Joung Kim, Seung-Hyun Jung, Yong-Rim Kwon, Sug Hyung Lee, Kyoo-Hyung Lee, Eun-Ji Choi, Eun-Hye Hur, Yeun-Jun Chung, Je-Hwan Lee, Yoo-Jin Kim, Silvia Park, and Hyeon-Chun Park
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Adult ,Male ,Oncology ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,medicine.medical_specialty ,Adolescent ,DNA Copy Number Variations ,Somatic cell ,Disease-Free Survival ,DNA sequencing ,Deep sequencing ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Internal medicine ,Complex Karyotype ,medicine ,Humans ,Child ,Gene ,Aged ,business.industry ,High-Throughput Nucleotide Sequencing ,Hematology ,Middle Aged ,Neoplasm Proteins ,Survival Rate ,Leukemia, Myeloid, Acute ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Mutation ,Female ,business ,030215 immunology - Abstract
Background: Recent advancements in next-generation sequencing (NGS) technologies allow the simultaneous identification of targeted copy number alterations (CNAs) as well as somatic mutations using the same panel-based NGS data. We investigated whether CNAs detected by the targeted NGS data provided additional clinical implications, over somatic mutations, in myelodysplastic syndrome (MDS). Methods: Targeted deep sequencing of 28 well-known MDS-related genes was performed for 266 patients with MDS. Results: Overall, 215 (80.8%) patients were found to have at least one somatic mutation; 67 (25.2%) had at least one CNA; 227 (85.3%) had either a somatic mutation or CNA; 160 had somatic mutations without CNA; and 12 had CNA without somatic mutations. Considering the clinical variables and somatic mutations alone, multivariate analysis demonstrated that sex, revised International Prognostic Scoring System (IPSS-R) and NRAS and TP53 mutations were independent prognostic factors for overall survival. For AML-free survival, these factors were sex, IPSS-R, and mutations in NRAS, DNMT3A, and complex karyotype/TP53 mutations. When we consider clinical variables along with somatic mutations and CNAs, genetic alterations in TET2, LAMB4, U2AF1, and CBL showed additional significant impact on the survivals. Conclusions: Our study suggests that the concurrent detection of somatic mutations and targeted CNAs may provide clinically useful information for the prognosis of MDS patients.
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- 2021
17. Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
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Bon-Kwan Goo, Yong-Rim Kwon, Seung-Hyun Jung, Yunsuk Choi, Je-Hwan Lee, Eun-Hye Hur, Sug Hyung Lee, Yeun-Jun Chung, Yoo-Jin Kim, Hye-Jung Kim, and Seon-Hee Yim
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Adult ,Male ,0301 basic medicine ,Oncology ,Gerontology ,medicine.medical_specialty ,Multivariate analysis ,Somatic cell ,Azacitidine ,Subgroup analysis ,medicine.disease_cause ,DNA Methyltransferase 3A ,Dioxygenases ,hypomethylating therapy ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,Internal medicine ,Hypomethylating Therapy ,Humans ,Medicine ,In patient ,DNA (Cytosine-5-)-Methyltransferases ,targeted sequencing ,Aged ,Mutation ,business.industry ,Myelodysplastic syndromes ,DNA Methylation ,Middle Aged ,Genes, p53 ,Prognosis ,Splicing Factor U2AF ,medicine.disease ,myelodysplastic syndrome ,DNA-Binding Proteins ,Genes, ras ,030104 developmental biology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Female ,business ,Research Paper ,medicine.drug - Abstract
Although hypomethylating therapy (HMT) is the first line therapy in higher-risk myelodysplastic syndromes (MDS), predicting response to HMT remains an unresolved issue. We aimed to identify mutations associated with response to HMT and survival in MDS. A total of 107 Korean patients with MDS who underwent HMT (57 responders and 50 non-responders) were enrolled. Targeted deep sequencing (median depth of coverage 1,623X) was performed for 26 candidate MDS genes. In multivariate analysis, no mutation was significantly associated with response to HMT, but a lower hemoglobin level (
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- 2016
18. DDX41 mutation in Patients with Idiopathic Cytopenia of Undetermined Significance, Myelodysplastic Syndrome, and Acute Myeloid Leukemia
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Je-Hwan Lee, Nayoung Kim, Eun-Hye Hur, Han-Seung Park, Seongsoo Jang, Chan-Jeoung Park, Eun-Ji Choi, Hee Jeong Ouk, Young-Uk Cho, Jung-Hee Lee, and Kyoo Hyung Lee
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Oncology ,Cytopenia ,Mutation ,medicine.medical_specialty ,Myeloid ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Germline ,medicine.anatomical_structure ,Germline mutation ,International Prognostic Scoring System ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business - Abstract
Background Following the advances in genetic tests, including next-generation sequencing, there have been new insights into hereditary hematopoietic malignancies. The germline mutation in DDX41 was included in a new category, myeloid neoplasms with germline predisposition, of the updated 2016 WHO classification. Based on the reported data to date, there seem to be racial differences in the mutation variants of DDX41 gene, which were found in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Idiopathic cytopenia of undetermined significance (ICUS) is known to be a precursor lesion of MDS, but the DDX41 mutations have not been evaluated in patients with ICUS. In this study, we aimed to reveal the incidence, genetic characteristics, and clinical features of the DDX41 mutations in patients with ICUS, MDS, and AML. Methods We performed targeted deep sequencing of 141 genes with a MiSeqDx sequencer (Illumina) using bone marrow (BM) samples obtained from the patients with ICUS (n=77), MDS (n=175), and AML (n=148) between May 2009 and June 2019. ICUS was defined by the proposed criteria of 2007 Consensus Group. The cut-off level of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. We divided ICUS into clonal cytopenia of undetermined significance (CCUS), which was defined as ICUS with ≥ 2% VAF of somatic mutations of myeloid malignancy-associated genes and non-CCUS. Results Overall, DDX41 mutations were detected in 6 (7.8%) of 77 ICUS, 19 (10.9%) of 175 MDS, and 8 (5.4%) of 148 AML patients. Thirty-eight (49.4%) of 77 ICUS patients had CCUS. Of 6 DDX41 mutated patients with CCUS, 5 showed biallelic mutations with the median VAF of 44.7% (range, 29.3−50.0) and 10.2% (range, 3.3−25.4), indicating that one germline and one somatic mutation exists. Of 175 MDS patients, 78 were categorized into lower-risk MDS (revised international prognostic scoring system [IPSS-R] < 3.5) and 97 into higher-risk MDS (IPSS-R ≥ 3.5), and DDX41 mutations were identified in 6 (7.7%) of 78 lower-risk MDS and 13 (13.4%) of 97 higher-risk MDS patients. Interestingly, biallelic mutations were found in 16 of 18 DDX41-mutated MDS patients with the median VAF of 47.75% (range, 43.4−55.6) and 13.8% (range, 2.7−35.8). In contrast, only one of 8 DDX41-mutated AML patients had biallelic mutation. Patients with DDX41 mutations typically showed hypocellular marrow (median BM cellularity, 30%; range, 5−95) with significant neutropenia (median neutrophil counts, 607/μL; range, 142−1675), male predominance (29/33, 87.9%), and relatively older age (median age, 64 years; range, 41−79) at diagnosis. In addition, we found novel mutation locations, which were different between presumed germline and somatic variants: V152G in germline, and T227M in somatic (Table 2). During a median follow-up duration of 2.9 years, 1 of 6 ICUS patients progressed to MDS-EB-1 after 17.3 months and 1 to non-severe aplastic anemia after 51.3 months. Conclusion Our data show that a significant proportion of ICUS, MDS, and AML patients had DDX41 mutations, many of which are presumably germline. These findings suggest that careful consideration of the predisposing germline mutation is important when selecting a familial donor for allogeneic HCT. We also found novel mutation locations of DDX41 gene which were different between somatic and germline variants. Further studies are warranted to define the clinical and molecular characteristics of DDX41 mutations and therapeutic implications in myeloid neoplasms. Disclosures No relevant conflicts of interest to declare.
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- 2019
19. Mutational Characteristics and Changing Pattern from Idiopathic Cytopenia of Undetermined Significance to High-Risk Myelodysplastic Syndrome Stratified By IPSS-R
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Je-Hwan Lee, Eun-Ji Choi, Han-Seung Park, Eun-Hye Hur, Chan-Jeoung Park, Nayoung Kim, Jung-Hee Lee, Hee Jeong Ouk, Young-Uk Cho, Kyoo-Hyung Lee, and Seongsoo Jang
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Oncology ,Cytopenia ,medicine.medical_specialty ,Mutation ,IDH1 ,business.industry ,Immunology ,Disease progression ,Cell Biology ,Hematology ,Disease ,medicine.disease ,medicine.disease_cause ,Biochemistry ,ETV6 ,International Prognostic Scoring System ,hemic and lymphatic diseases ,Internal medicine ,medicine ,KRAS ,business - Abstract
Background: Unexplained cytopenia comprises a spectrum of hematological diseases from idiopathic cytopenia of undetermined significance (ICUS) to myelodysplastic syndrome (MDS). Revised International Prognostic Scoring System (IPSS-R) is the standard tool to assess risk in MDS. Here, we investigated the occurrence, characteristics, and changing pattern of mutations in patients with ICUS and MDS stratified by IPSS-R score. Methods: A total of 211 patients were enrolled: 73 with ICUS and 138 with MDS. We analyzed the sequencing data of a targeted gene panel assay covering 141 genes using the MiSeqDx platform (Illumina). The lower limit of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Bone marrow components were assessed for the revised diagnosis according to the 2016 WHO classification. Lower-risk (LR) MDS was defined as those cases with very low- or low-risk MDS according to the IPSS-R. Higher-risk (HR) MDS was defined as those cases with high- or very high-risk MDS according to the IPSS-R. Results: Patients with ICUS were classified as very low-risk (39.7%), low-risk (54.8%), and intermediate-risk (5.5%) according to the IPSS-R. Patients with MDS were classified as LR (35.5%), intermediate-risk (30.4%), and HR (34.1%). In the ICUS, 28 (38.4%) patients carried at least one mutation in the recurrently mutated genes in MDS (MDS mutation). The most commonly mutated genes were DNMT3A (11.0%), followed by TET2 (9.6%), BCOR (4.1%), and U2AF1, SRSF2, IDH1 and ETV6 (2.7% for each). IPSS-R classification was not associated with mutational VAF and the number of mutations in ICUS. In the 49 LR MDS, 28 (57.1%) patients carried at least one MDS mutation. The most commonly mutated genes were SF3B1 (20.4%), followed by TET2 (12.2%), U2AF1 (10.2%), DNMT3A (10.2%), ASXL1 (10.2%), and BCOR (6.1%). Higher VAF and number of mutations were observed in LR MDS compared to ICUS patients. In the 42 intermediate-risk MDS, 27 (64.3%) patients carried at least one MDS mutation. The most commonly mutated genes were ASXL1 (23.8%), followed by TET2 (21.4%), RUNX1 (16.7%), U2AF1 (14.3%), DNMT3A (14.3%), SF3B1 (9.5%), and SRSF2, BCOR, STAG2 and CBL (7.1% for each). In the 47 HR MDS, 36 (76.6%) patients carried at least one MDS mutation. The most commonly mutated genes were TET2 (25.5%), followed by DNMT3A (14.9%), TP53 (14.9%), RUNX1 (12.8%), U2AF1 (10.6%), ASXL1 (10.6%), and SRSF2 and KRAS (6.4% for each). As the disease progressed, VAF and number of the MDS mutations gradually increased, and mutations involving RNA splicing, histone modification, transcription factor or p53 pathway had a trend for increasing frequency. Specifically, ASXL1, TP53, and RUNX1 mutations were the most striking features in patients with advanced stage of the disease. Cohesin mutations were not detected in ICUS, whereas these mutations were detected at a relatively high frequency in HR MDS. Our data were summarized in Table 1. Conclusions: We demonstrate that on disease progression, MDS mutations are increased in number as well as are expanded in size. Furthermore, a subset of mutations tends to be enriched for intermediate- to HR MDS. The results of this study can aid both diagnostic and prognostic stratification in patients with unexpected cytopenia. In particular, characterization of MDS mutations can be useful in refining bone marrow diagnosis in challenging situations such as distinguishing LR MDS from ICUS. Disclosures No relevant conflicts of interest to declare.
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- 2019
20. Clinical Implications of Copy Number Variant Detection from Panel-Based Next-Generation Sequencing Data in Myelodysplastic Syndrome
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Seon-Hee Yim, Kyoo Hyung Lee, Yong-Rim Kwon, Eun-Ji Choi, Je-Hwan Lee, Sug Hyung Lee, Seung-Hyun Jung, Young-Woo Jeon, Yeun-Jun Chung, Hye-Jung Kim, Yoo-Jin Kim, and Eun-Hye Hur
- Subjects
Univariate analysis ,Immunology ,Neutrophil collagenase ,Cell Biology ,Hematology ,Computational biology ,Biology ,Biochemistry ,DNA sequencing ,Log-rank test ,Copy Number Polymorphism ,Copy-number variation ,Bone marrow specimen ,Protein p53 - Abstract
Some of the recurrently occurring somatic mutations are known to be diagnostic or prognostic in myelodysplastic syndrome (MDS). Targeted gene capture and next-generation sequencing (NGS) has rapidly become routine clinical tools to detect the somatic mutations in patients with MDS. Copy number variants (CNVs) may have additional clinical significance in MDS. Chromosomal microarray analysis is a standard technique for genome-wide CNV detection, but multiple testing strategies require high costs and time. Recent advancements in NGS technologies have developed more cost-effective and rapid methods to allow simultaneous identification of targeted CNVs as well as somatic mutations using the same panel-based NGS data. In this study, we investigated whether the detection of CNVs using the targeted NGS data provided an additional value other than the clinical implications of somatic mutations. We performed targeted deep sequencing analysis on bone marrow samples obtained from 266 patients with MDS using an MDS panel targeting 28 well-known MDS-related genes (NRAS, DNMT3A, SF3B1, IDH1, TET2, NPM1, LAMB4, EZH2, JAK2, CBL, ETV6, KRAS, FLT3, IDH2, PRPF8, TP53, NF1, SRSF2, SETBP1, DNMT1, ASXL1, RUNX1, U2AF1, ZRSR2, ATRX, STAG2, MMP8, and ARID2). Sequencing libraries were generated using the AmpliSeq Library Kit 2.0 (Life Technologies, Carlsbad, CA) and the MDS panel was then sequenced using the Ion Torrent Proton system (Life Technologies) according to the manufacturer's instructions. The multiscale reference module and Rank Segmentation statistical algorithm in NEXUS software v9.0 (Biodiscovery) were used to define the CNVs for each sample. Overall survival (OS) and acute myeloid leukemia (AML)-free survival (AFS) were estimated from the date of MDS diagnosis to death or AML progression using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test (for univariate analysis) and the Cox proportional hazards model (for multivariate analysis). Overall, 215 patients (80.8%) carried at least one somatic mutations, and 67 (25.2%) had one or more CNVs. The number of mutated genes per patient ranged from 0 to 6, and the number of genes with CNVs per patient ranged from 0 to 10. Of 51 patients who did not have somatic mutations, 12 (23.5%) had the targeted CNVs. The mutated genes in more than 10% of patients were 8: U2AF1 (21.8%), TET2 (17.7%), ASXL1 (13.5%), TP53 (13.2%), SETBP1 (12.8%), NF1 (10.9%), SF3B1 (10.5%), and RUNX1 (10.5%). The genes with CNVs detected in 10 or more patients were 5: EZH2 (loss in 7q, 6.8%), KRAS (gain and loss in 12p, 5.3%), ASXL1 (gain and loss in 20q, 4.5%), LAMB4 (loss in 7q, 3.8%), and RUNX1 (gain and loss in 21q, 3.8%). Interestingly, all five patients with TP53 deletion exhibited TP53 mutation as well, suggesting a bi-allelic alteration (mutation + copy loss). The higher number of genes with CNVs per patient were significantly associated with inferior OS (P Our study suggests that simultaneous detection of targeted CNVs as well as somatic mutations using the same panel-based NGS data add clinically useful information on the prognosis of MDS patients. Disclosures No relevant conflicts of interest to declare.
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- 2019
21. TP53 mutation in allogeneic hematopoietic cell transplantation for de novo myelodysplastic syndrome
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Sug Hyung Lee, Seung-Hyun Jung, Yoo-Jin Kim, Eun-Ji Choi, Yong-Rim Kwon, Yeun-Jun Chung, Hye-Jung Kim, Kyoo-Hyung Lee, Seon-Hee Yim, Eun-Hye Hur, Je-Hwan Lee, and Young-Woo Jeon
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Graft vs Host Disease ,medicine.disease_cause ,Gastroenterology ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Humans ,Cumulative incidence ,Risk factor ,Aged ,Mutation ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,De novo Myelodysplastic Syndrome ,High-Throughput Nucleotide Sequencing ,Hematology ,Middle Aged ,Allografts ,Transplantation ,Survival Rate ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Female ,Bone marrow ,Tumor Suppressor Protein p53 ,business ,030215 immunology - Abstract
We investigated the prognostic role of somatic mutations in allogeneic hematopoietic cell transplantation (HCT) for de novo myelodysplastic syndrome (MDS). We performed targeted deep sequencing analysis of 26 genes on bone marrow samples obtained within 6 weeks before HCT from 202 patients with de novo MDS. Overall, 76% of patients carried one or more somatic mutations, and TP53 mutation was present in 23 patients (11.4%). Overall survival (OS) at 5 years was 63.6%, cumulative incidence of relapse (CIR) was 18.6%, event-free survival (EFS) was 58.5%, and non-relapse mortality (NRM) was 22.9%. TP53 mutation was an independent risk factor for lower OS (41% vs. 67%; P = 0.001), higher CIR (49% vs. 15%; P = 0.001), and lower EFS (38% vs. 61%; P = 0.005), but not for NRM (13% vs. 24%). N-RAS mutation was an independent risk factor for higher CIR (HR, 5.91; P = 0.008). TP53 mutation did not have significant interactions with conditioning intensity or the occurrence of graft-versus-host disease with regard to post-transplant outcomes. In conclusion, TP53 mutation was significantly associated with poor outcomes after HCT for patients with de novo MDS, mainly due to a higher incidence of disease relapse.
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- 2018
22. Selective toxicity on canine blood cells by using atmospheric-pressure plasma jets
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Eun-Hye Hur, Yong Hee Kim, and Ku Youn Baik
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medicine.diagnostic_test ,Chemistry ,General Physics and Astronomy ,Complete blood count ,Atmospheric-pressure plasma ,In vitro ,Blood cell ,medicine.anatomical_structure ,Apoptosis ,Cancer cell ,Toxicity ,medicine ,Biophysics ,Platelet - Abstract
Atmospheric pressure plasma jets have received increasing attention due to their non-thermal effects on biological samples. Their noticeable sterilization on tissues, selective apoptosis of cancer cells and effective regeneration of damaged tissues have successfully demonstrated their medical applicability. However, the side effects or toxic effects on normal cells should be investigated fully before real applications. In this study, we report the selective toxicity of atmospheric pressure plasma jets (APPJ) on blood cells in vitro for the first time. A complete blood cell count is used to count and size the blood cells statistically. We found gas- and time-dependent effects of APPJ exposure on the number ratios and the size distributions of red blood cells, white blood cells and platelets.
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- 2012
23. Single nucleotide polymorphism of Wilms’ tumor 1 gene rs16754 in Korean patients with cytogenetically normal acute myeloid leukemia
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Kyoo Hyung Lee, Kyun-Seop Bae, Yunsuk Choi, Sung Nam Lim, Sung-Doo Kim, Dae-Young Kim, Young A. Kang, Hyeong Seok Lim, Miee Seol, Eun-Hye Hur, Jung-Hee Lee, Je-Hwan Lee, and M. Kang
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Adult ,Male ,medicine.medical_specialty ,Myeloid ,Adolescent ,Genotype ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Gastroenterology ,Young Adult ,Asian People ,Gene Frequency ,Internal medicine ,Republic of Korea ,medicine ,Humans ,SNP ,WT1 Proteins ,Allele frequency ,Aged ,Exons ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Genotype frequency ,Minor allele frequency ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Mutation ,Immunology ,Female - Abstract
A recent study from Germany showed that WT1 single nucleotide polymorphism (SNP) rs16754 was an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML). We analyzed clinical impact of the WT1 rs16754 genotype on disease characteristics and outcomes in Korean patients with CN-AML. A total of 73 patients with CN-AML were included in the study. All patients received standard induction chemotherapy and their bone marrow or peripheral blood samples were cryopreserved at the time of diagnosis. WT1 exons 7 and 9 were amplified using polymerase chain reaction and directly sequenced. The genotype frequency for WT1 rs16754 was 6.8% for AA, 39.7% for GA, and 53.4% for GG. G was a minor allele in German population, whereas it was a major allele in Korean (13.7% vs. 73.3%, P
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- 2011
24. Influence of Environmental Conditions on c-Jun N-terminal Kinase Mediated Apoptosis of HL60 Cells by Anti-Cancer Drugs
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M. Kang, Eun-Hye Hur, Dae-Young Kim, Sung Nam Lim, Je-Hwan Lee, Sung-Doo Kim, Kyoo Hyung Lee, and Jung-Hee Lee
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Pharmacology ,Caspase-9 ,Daunorubicin ,HL60 ,c-jun ,Caspase 3 ,Biology ,Caspase 8 ,Biochemistry ,Molecular biology ,chemistry.chemical_compound ,chemistry ,Apoptosis ,Drug Discovery ,Cancer research ,medicine ,biology.protein ,Molecular Medicine ,Fetal bovine serum ,medicine.drug - Abstract
- Activation of JNK has long been associated with the apoptotic response induced by various anti-cancer drugs including doxorubicin, vinblastine, and etoposide. In this study, we examined and compared patterns of apoptosis and JNK activation according to three different anti-cancer drugs (daunorubicin, vinblastine, and etoposide) and two different sources of HL60 cells (Jackson Laboratory and ATCC). HL60 cells from Jackson Laboratory (HL60/RPMI) were maintained in RPMI 1640 containing 5% fetal bovine serum and those from ATCC (HL60/IMDM) in IMDM containing 20% fetal bovine serum as to each manufacture’s guideline. In general, HL60/RPMI cells were more sensitive to anti-cancer drugs compared to HL60/IMDM cells, demonstrated by the XTT and flow cytometric analyses. Apoptotic pathways after treatment with anti-cancer drugs seemed to be different between HL60/RPMI (daunorubicin and etoposide, caspase 3 dependent, but caspase 8 or 9 independent; vinblastine, caspase 3 independent) and HL60/IMDM (caspase 3 and caspase 9 dependent). The expression of apoptotic protein, BID, was consistent with caspase 3 activation. Immunoblotting of phospho-JNK and JNK kinase assay showed JNK activation by all three anti-cancer drugs in HL60/RPMI, while JNK activation was observed only in vinblastine-treated cells in HL60/IMDM. Our study results suggest that in vitro environmental conditions have a significant influence on JNK mediated apoptosis of HL60 cells by anti-cancer drugs and in vitro culture conditions are important factors in JNK or possibly other MAPK related studies.Keywords: JNK, Anticancer drugs, HL60
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- 2010
25. Clinical significance of GSTM1 and GSTT1 polymorphisms in younger patients with acute myeloid leukemia of intermediate-risk cytogenetics
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Eun-Hye Hur, Miee Seol, Se Hyung Kim, Yang Soo Kim, Sol-Ip Kang, Young-Shin Lee, Kyoo-Hyung Lee, Chan Jeoung Park, Jung-Hee Lee, Young-Ah Kang, Michael Jinpyo Lee, M. Kang, Hyun Sook Chi, Je-Hwan Lee, Sung-Cheol Yun, Seongsoo Jang, Ho Sup Lee, Eul-Ju Seo, Seong-Gil Ryu, and Dae-Young Kim
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Biology ,Gstm1 polymorphism ,Disease-Free Survival ,Young Adult ,Recurrence ,Risk Factors ,Internal medicine ,Genotype ,medicine ,Humans ,Cumulative incidence ,In patient ,Clinical significance ,Glutathione Transferase ,Polymorphism, Genetic ,Age Factors ,Cytogenetics ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Cytogenetic Analysis ,Immunology ,Female ,Intermediate risk - Abstract
We investigated the association between GSTM1 or GSTT1 polymorphisms and clinical outcomes in 133 younger patients with AML of intermediate-risk cytogenetics. Clinical outcomes were not significantly different among the GSTM1 polymorphism genotypes, whereas cumulative incidence of relapse (CIR) was significantly lower and event-free survival (EFS) was significantly higher in patients with the GSTT1 -present genotype compared with those with the GSTT1 -null genotype (CIR at 5 year, 28.9% vs. 44.6%, P = 0.018; EFS at 5 year, 51.4% vs. 34.1%, P = 0.029). Our results suggest that GSTT1 gene polymorphism has significant clinical implications in younger patients with AML of intermediate-risk cytogenetics.
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- 2009
26. Expression of JL1 Antigen in Acute Leukemia and Myelodysplastic Syndrome
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Jung-Hee Lee, Eun-Ji Choi, Han-Seung Park, Dae-Young Kim, Kyoo-Hyung Lee, Soseul Kim, Je-Hwan Lee, Kyeongcheon Jung, Chan-Jeoung Park, Sangsoon Yoon, and Eun-Hye Hur
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Oncology ,medicine.medical_specialty ,NPM1 ,Acute leukemia ,business.industry ,Immunology ,CD34 ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,Antigen ,hemic and lymphatic diseases ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Cytarabine ,business ,medicine.drug - Abstract
Background: The JL1 antigen is a novel epitope of CD43, a cell surface glycoprotein of mucin family. JL1 is a differentiation antigen expressed on stage II double positive (CD4+CD8+) human cortical thymocytes. The antigen is not expressed on mature peripheral blood cells or other normal tissues. The anti-JL1 monoclonal antibody binds to human leukemia MOLT-4 cells with 5,100-9,600 binding sites per cell. Preclinical studies have shown the cytotoxic effects of anti-JL1-based immunotoxin against JL1-positive leukemic cells, sparing most normal tissues other than thymocytes and some bone marrow mononuclear cells. Phase I clinical trial of new anti-leukemic agent with an anti-JL1 antibody (Leukotuximab; DiNonA, Korea) is now underway. In this study, we prospectively investigated the JL1 expression in patients with acute leukemia and myelodysplastic syndrome (MDS). Patients & methods: Flow cytometric analysis for the JL1 expression on leukemic blasts was performed using a FACSCanto II (Becton-Dickinson, Sunnyvale, CA, USA). The percent expression of JL1 antigen among leukemic blasts was recorded. Positive JL1 expression was defined if 20% or more leukemic blasts expressed the antigen. Association of JL1 expression with clinical, pathologic, and genetic characteristics was analyzed. Influence of JL1 expression on clinical outcomes of patients was also explored. Results: Between March 2014 and June 2015, a total of 245 adult patients with acute myeloid leukemia (AML, n=170), acute lymphoblastic leukemia (ALL, n=52), and MDS (n=23) were enrolled in this study. Positive JL1 expression was observed in 96 (57.1%) patients with AML, 28 (51.9%) with ALL, and 5 (21.7%) with MDS (P =0.006), while three normal controls showed negative JL1 antigen expression. Interestingly, JL1 expression was positive in all 14 patients with AML M3 with a median expression of 94.3% (range, 60.3-97.8%). In contrast, only 13 (39.4%) of 33 patients with AML with myelodysplasia-related changes (MRC) had positive JL1 expression. In AML patients, positive JL1 expression was significantly associated with CD34- (P =0.003), HLA-DR- (P =0.019), PML-RARA + (P =0.001), FLT3-ITD + (P =0.026), mutated NPM1 (P =0.003), and complex karyotype (3 or more clonal chromosomal abnormalities) (P =0.020). Cytarabine plus anthracycline based chemotherapy was given to 117 patients with AML, and the complete remission (CR) rate was significantly different between 63 JL1 expression positive patients and 54 negative patients (84.1% vs. 59.3%, P =0.003). Positivity of JL1 expression was not significantly associated with overall survival in all patients with AML (median survival, JL1 positive vs. negative, 20.6 vs. 18.2 months, P =0.489). In ALL patients, positive JL1 expression was significantly associated with CD13- (P =0.032) and the CR rate was not significantly different by JL1 expression. JL1 expression was measured twice or more in 85 patients during their clinical courses and positivity of JL1 expression was not changed in 61 (71.8%) (P =0.307). Five MDS patients progressed to AML and JL1 expression was changed in only one patient (JL1 positive to JL1 negative). Conclusion: JL1 was expressed in around 50% of patients with AML or ALL while less frequent expression of JL1 was observed in MDS and AML with MRC. JL1 expression was significantly associated with some immunophenotypic and genetic features, especially PML-RARA +. JL1 expression was significantly associated with the CR rate of AML patients. Expression of JL1 seems to be stable during clinical courses. Our data suggest that immunotherapeutic approach targeting JL1 antigen may be feasible in significant proportion of patients with acute leukemia and MDS. Disclosures Kim: Dinona Institute, Dinona Inc.: Employment. Yoon:Dinona Institute, Dinona Inc.: Employment. Jung:Dinona Institute, Dinona Inc.: Employment.
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- 2015
27. C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia
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Soo-Kyung Shim, Je-Hwan Lee, Jung-Hee Lee, Hee-Jung Lee, Kyoo-Hyung Lee, M. Kang, Seong-Gil Ryu, Young-Shin Lee, Chan-Jeoung Park, Yae Eun Jang, Michael Jinpyo Lee, Miee Seol, Hyun-Sook Chi, Eun-Hye Hur, Ip-Sol Kang, Seong-Jun Choi, and Young-Ah Kang
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Adult ,Male ,Cancer Research ,ATP Binding Cassette Transporter, Subfamily B ,Genotype ,Polymorphism, Single Nucleotide ,Medicine ,Humans ,In patient ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,neoplasms ,P-glycoprotein ,C3435t polymorphism ,biology ,business.industry ,Myeloid leukemia ,Hematology ,Mdr1 gene ,Survival Analysis ,Genotype frequency ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,Immunology ,biology.protein ,Female ,Genes, MDR ,business ,Leukemic Blasts - Abstract
We investigated the association between the MDR1 C3435T polymorphism and P-glycoprotein function of leukemic blasts as well as clinical outcomes in 200 patients with AML, excluding the M3 subtype. The CC, CT and TT genotype frequencies of the C3435T polymorphism among patients were 71, 93 and 36, respectively. The C3435T polymorphism genotypes did not have influence on the P-glycoprotein function of leukemic blasts. Complete remission rates and overall, relapse-free and event-free survival rates were not significantly different among the C3435T polymorphism genotypes. In conclusion, the MDR1 C3435T polymorphism does not appear to have significant clinical implications in AML.
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- 2007
28. 161 CYTOGENETIC CHARACTERIZATION OF AZACITIDINE-RESISTANT CELL LINE (MOLM/AZA-1) ESTABLISHED FROM AML/MDS CELL LINE (MOLM-13)
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Yunsuk Choi, Yonggoo Kim, Seung-Hyun Jung, Eun Young Choi, Eun-Hye Hur, Juhyun Moon, Jung-Shin Lee, Bon-Kwan Goo, and Yeun-Jun Chung
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Cancer Research ,Oncology ,Chemistry ,Cell culture ,Azacitidine ,medicine ,Cancer research ,Hematology ,Line (text file) ,Resistant cell ,medicine.drug - Published
- 2015
29. Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia.
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Je-Hwan Lee, Hawk Kim, Young-Don Joo, Won-Sik Lee, Sung Hwa Bae, Dae Young Zang, Jihyun Kwon, Min Kyoung Kim, Junglim Lee, Gyeong Won Lee, Jung-Hee Lee, Yunsuk Choi, Dae-Young Kim, Eun-Hye Hur, Sung-Nam Lim, Sang-Min Lee, Hun Mo Ryoo, Hyo Jung Kim, Myung Soo Hyun, and Kyoo-Hyung Lee
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- 2017
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30. Functional identification of the pro-apoptotic effector domain in human Sox4
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In-Kyung Kim, Ju-Youn Choi, Seung Kew Yoon, Hyangshuk Rhim, Eun Hye Hur, Wonhee Hur, and Ho-Youn Kim
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Transcriptional Activation ,Programmed cell death ,Molecular Sequence Data ,Biophysics ,Apoptosis ,Biology ,medicine.disease_cause ,Biochemistry ,Cell Line ,SOXC Transcription Factors ,SOX4 ,medicine ,Humans ,Amino Acid Sequence ,Molecular Biology ,Effector ,High Mobility Group Proteins ,Cell Biology ,DNA-binding domain ,Protein Structure, Tertiary ,High-mobility group ,Cell culture ,Cancer research ,Trans-Activators ,Carcinogenesis - Abstract
Recent studies provide evidence that Sox4 is involved in regulating apoptosis as well as tumorigenesis of various human cancers; however, its role in the apoptotic machinery is not fully understood. Here we describe that the central domain containing glycine-rich region in Sox4, named CD, is a pivotal pro-apoptotic domain to induce apoptotic cell death. Deletion of the DNA-binding domain or trans-activation domain in Sox4 did not significantly affect pro-apoptotic activity, whereas transient transfection of the high mobility group box or the serine-rich region abrogated the apoptotic activity. Moreover, overexpression of the CD construct (aa 166-342) revealed the apoptotic activity comparable to that of wild-type Sox4, approximately 60% of cell death. Our data suggest that the apoptotic activity of Sox4 can be dissociated from its transcriptional trans-activation and is mediated through its CD.
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- 2004
31. Rapid purification and analysis of alpha-synuclein proteins: C-terminal truncation promotes the conversion of alpha-synuclein into a protease-sensitive form in Escherichia coli
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Seongman Kang, Hyangshuk Rhim, Chul Hahn, In Kyung Kim, Hyo Jin Park, Young Mo Sung, Sun Joo Lee, Byung Re Min, Eun Hye Hur, and Ju Youn Choi
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medicine.medical_treatment ,Recombinant Fusion Proteins ,Biomedical Engineering ,Synucleins ,Bioengineering ,Nerve Tissue Proteins ,Biology ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,chemistry.chemical_compound ,Drug Discovery ,Gene expression ,medicine ,Escherichia coli ,Glutathione Transferase ,Alpha-synuclein ,chemistry.chemical_classification ,Regulation of gene expression ,Protease ,Process Chemistry and Technology ,General Medicine ,Gene Expression Regulation, Bacterial ,Fusion protein ,nervous system diseases ,Enzyme ,nervous system ,chemistry ,Biochemistry ,Synuclein ,alpha-Synuclein ,Molecular Medicine ,Biotechnology - Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons and the formation of eosinophilic intracytoplasmic inclusion bodies known as Lewy bodies. Although alpha-synuclein is known to be a pivotal factor implicated in the pathogenesis of PD, its function remains to be elucidated. We used the pGEX expression system to develop a simple and rapid method for purifying alpha-synuclein proteins in suitable forms for biochemical studies of their functions. The wild-type alpha-synuclein protein was overexpressed in Escherichia coli and purified to approx. 80% purity with relatively high yields. We also used this expression system to investigate the expression pattern of the various domains of alpha-synuclein. With the exception of the alpha-synuclein protein that was truncated at amino acid residue 95, all domain constructs of alpha-synuclein were purified at similar levels with relatively high yields. Unexpectedly, removal of amino acid residues 96-140 in the C-terminal acidic region of alpha-synuclein promotes its conversion to a protease-sensitive form during expression and purification in E. coli. Our study suggests a method for generating useful reagents to investigate the molecular mechanism by which alpha-synuclein regulates the pathogenesis of PD.
- Published
- 2002
32. Abstract 1499: Expression and prognostic significance of microRNAs in Korean patients with myelodysplastic syndrome
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Je-Hwan Lee, Bon-Kwan Goo, Dae R. Choi, Yunsuk Choi, Eun-Hye Hur, and Ju Hyun Moon
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Regulation of gene expression ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Chronic myelomonocytic leukemia ,Cancer ,Translational Inhibition ,medicine.disease ,Bioinformatics ,Peripheral blood mononuclear cell ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,microRNA ,medicine ,Bone marrow ,Stage (cooking) ,business - Abstract
Introduction: MicroRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional regulation of gene expression, which may result in translational inhibition or destabilization of the target mRNA. Various alterations of miRNA expression have been reported in myelodysplastic syndrome (MDS). We aimed to investigate the unique patterns and prognostic significance of miRNA expression in Korean patients with MDS. Materials and Methods: Bone marrow mononuclear cells were collected from 10 healthy controls and 26 MDS patients, and miRNAs were isolated using a miRNeasy isolation kit (Qiagen) according to the manufacturer's instructions. Quantitative real-time PCR for selected miRNAs including miR-21, miR-124a, miR-126, miR-146b, miR-155, miR-200c, miR-342-5p, miR-708, and Let-7a was performed using a miScript SYBR green PCR kit (Qiagen). RNU6 was used to normalize the miRNA values of all RNA samples. Calculations were made using the comparative Ct (2-ΔΔCt ) method. Results: Eleven patients with early stage MDS (2 RA, 1 RARS, and 8 RCMD), 10 patients with advanced MDS (3 RAEB-1 and 7 RAEB-2), 4 patients with unknown subtype of MDS, and 1 patient with chronic myelomonocytic leukemia were included in this study. Median age was 58.5 years (range, 13-76). MiR-124a, miR-155, miR-200c, miR-342-5p, and let-7a were significantly under-expressed in MDS patients compared to healthy controls. Levels of miR-124, miR-146b, and miR-155 transcripts were significantly lower in patients with early stage MDS than in those with advanced MDS. Secondary MDS patients (n=6) showed significantly under-expressed MiR-146b and miR-342-5p transcript levels than de novo MDS patients (n=19) (p=0.009 and p=0.043, respectively). We failed to find statistically significant survival differences according to the expression levels of miRNAs, although high expression of miR-124, miR-126, miR-155 and low expression of miR-342-5p tended to be associated with poor overall survival and leukemia free survival. Conclusion: We first report under-expression of miR-200c in MDS patients. Expression of miRNAs appears to be different according to the stage of MDS. Further investigations are needed to evaluate genetic functions and prognostic significances of miRNAs in MDS. Citation Format: Yunsuk Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Dae Ro Choi, Je-Hwan Lee. Expression and prognostic significance of microRNAs in Korean patients with myelodysplastic syndrome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1499. doi:10.1158/1538-7445.AM2014-1499
- Published
- 2014
33. Abstract 5455: Resistance to a MEK inhibitor (AZD6244): Its association with increased expression of transcription factor 4
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Suk Young Cho, Yunsuk Choi, Choung-Soo Kim, Sang-Hwa Yang, Jung Jin Hwang, Bon-Kwan Goo, Eun-Hye Hur, Jene Choi, Je-Hwan Lee, Kyun-Seop Bae, and Sung-Doo Kim
- Subjects
Genetics ,MAPK/ERK pathway ,Cancer Research ,Oncogene ,MEK inhibitor ,TCF4 ,Biology ,medicine.disease_cause ,Gene expression profiling ,Oncology ,Cancer research ,medicine ,Gene silencing ,Carcinogenesis ,Transcription factor - Abstract
The important role of Ras/Raf/MEK/ERK pathway in carcinogenesis has led to clinical development of MEK inhibitors for treatment of various cancers. Although recent studies have demonstrated impressive antitumor activities of the agents, many tumors show intrinsic and acquired resistance to MEK inhibitors. We tried to find biomarkers that were associated with intrinsic or acquired resistance to a MEK inhibitor (AZD6244) by public microarray data acquisition and development of AZD6244-resistance cell lines. First, we analyzed a set of genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines of various tissue origins to identify candidate genes whose expression changes are associated with resistant or sensitive responses to AZD6244. Of 62 differentially expressed genes, we selected Transcription Factor 4 (TCF4) gene as a potential drug resistance marker for further analysis because degree of increased expression of TCF4 in resistance cell lines was relatively high and a previous study suggests that TCF4 functions as an oncogene in human colon cancers. The mRNA levels of TCF4 in AZD6244 resistant cell lines were significantly elevated than those in sensitive cell lines. The siRNA was used for the targeted silencing of TCF4 to elucidate the role of increased expression of TCF4 in intrinsic resistance to AZD6244. TCF4 siRNA significantly enhanced susceptibility of a AZD6244-resistant cell line, LOXIMVI, to AZD6244. Next, we established AZD6244-resistant cell lines, using originally AZD6244-senstive cell lines, M14 and COLO-205. The half maximal inhibitory concentration (IC50) values for AZD6244 in two acquired resistant cell lines were 34 fold and 200 fold higher than those of their parent cell lines, respectively. Protein levels of TCF4 in the acquired resistant cell lines were higher than those in the sensitive parent cell lines. Our study results suggest that increase expression of TCF4 may be associated with both intrinsic and acquired resistance to MEK inhibitors. Citation Format: Bon-Kwan Goo, Eun-Hye Hur, Yunsuk Choi, Sung-Doo Kim, Jung Jin Hwang, Choung-Soo Kim, Kyun Seop Bae, Jene Choi, Suk Young Cho, Sang-Hwa Yang, Je-Hwan Lee. Resistance to a MEK inhibitor (AZD6244): Its association with increased expression of transcription factor 4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5455. doi:10.1158/1538-7445.AM2014-5455
- Published
- 2014
34. Abstract 399: Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13)
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Ju Hyun Moon, Je-Hwan Lee, Do Young Lee, Seonggu Ro, Eun-Hye Hur, Yunsuk Choi, Joong Myung Cho, Bon-Kwan Goo, and Dae R. Choi
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Cancer Research ,business.industry ,Myeloid leukemia ,Cancer ,medicine.disease ,XIAP ,Haematopoiesis ,Oncology ,Hypomethylating agent ,Cell culture ,Immunology ,medicine ,Cancer research ,Viability assay ,business ,Vorinostat ,medicine.drug - Abstract
Myelodysplastic syndrome (MDS) is a clonal disorder of the hematopoietic cells occurring in elderly patients in a majority of instances. They are defined by ineffective hematopoiesis with peripheral blood cytopenias and by the risk of evolution to acute myeloid leukemia (AML). Hypomethylating agents (HMA), 5-azacytidine (AZA) and 2-deoxy-5-azacytidine (DAC), have demonstrated clinical activities with cytologic and cytogenetic responses in patients with MDS, but potential problems of both agents include the development of intrinsic and acquired resistance. HMA-resistant patients have very poor prognosis, and this cohort of patients constitutes an important area of research. To understand mechanisms of HMA-resistance and overcome the resistance, we tried to establish HMA-resistant cells using MOLM-13, which is a cell line from a patient with AML evolved from MDS. Original MOLM-13 cell line was sensitive to both AZA and DAC in vitro. MOLM-13 cells were exposed continuously to increasing concetrations of AZA or DAC and we could establish an AZA-resistant cell line (MOLM/AZA-1) and a DAC-resistant cell line (MOLM/DAC-5). The IC50 of AZA in MOLM/AZA-1 was 96.26 µM compared to 0.11 µM of the parent cell line; 800-fold increase in resistance to AZA. The IC50 of DAC in MOLM/DAC-5 was 207.7 µM compared to 0.07 µM of the parent cell line; 2000-fold increase in resistance to DAC. We treated th AZA- and DAC-resistant cells with vorinostat (SAHA) and a novel agent, CG200745 to test whether the histone deacetylase (HDAC) inhibitors could overcome the HMA-resistance. Cell viability assays showed that HMA-resistant cells were sensitive to both HDAC inhibitors, which dramatically decreased anti-apoptotic proteins (XIAP, MCL-1 and BCL-2) and increased PARP cleavages in the HMA-resistant cell lines. In conclusion, we successfully established established AZA- and DAC-resistant cell lines from an AML/MDS cell line, MOLM-13, and found that HDAC inhibitors might be promising in overcoming HMA-resistance. Further studies with the HMA-resistant cell lines are ongoing for elucidation of resistance mechanisms and possible role of other novel agents to overcome the HMA-resistance. Citation Format: Dae Ro Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Yunsuk Choi, Do Young Lee, Seonggu Ro, Joong Myung Cho, Je-Hwan Lee. Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 399. doi:10.1158/1538-7445.AM2014-399
- Published
- 2014
35. Abstract 4666: Anti-leukemic activity of a novel histone deacetylase inhibitor, CG200745, via induction of mitochondrial dysfunction in acute myeloid leukemia
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Je-Hwan Lee, Kyoo-Hyung Lee, Minhee Kim, Yunsuk Choi, Seonggu Ro, Choung-Soo Kim, Junghee Lee, Eun-Hye Hur, Dae-Young Kim, Sung-Doo Kim, Jung Jin Hwang, and Bon-Kwan Goo
- Subjects
Cancer Research ,Cell growth ,HL60 ,medicine.drug_class ,Histone deacetylase inhibitor ,Myeloid leukemia ,Biology ,Molecular biology ,Romidepsin ,XIAP ,chemistry.chemical_compound ,Oncology ,chemistry ,medicine ,Viability assay ,Vorinostat ,medicine.drug - Abstract
Background: Acute myeloid leukemia (AML) can be cured by cytotoxic chemotherapy, but about half of patients with AML fail to obtain long-term survival, mostly due to chemotherapy-resistance. Novel therapeutic approaches are needed to overcome the resistance. Many studies have shown that histone deacetylase (HDAC) activity is elevated in human cancers and HDAC inhibitors (HDIs) induce expression of genes critical for tumor growth arrest and apoptosis. To date, the US FDA approves two HDIs, vorinostat (SAHA) and romidepsin (FK228), for treatment of cutaneous T-cell lymphoma. CG200745 {(E)-2-(Naphthalen-1-yloxymethyl)-oct-2-enedioic acid 1-[(3-dimethylamino-propyl)-amide] 8-hydroxyamide]} is a novel hydroxamate-based pan-HDI. We examined anti-leukemic activities of CG200745 in AML and we also compared the effects of CG200745 and SAHA in vitro and in vivo. Materials and methods: For cell proliferation assay, 7 human AML and other leukemia cell lines (HL60, K562, Molm13, MV4, NB4, U937, and KG-1) were cultured with HDIs (CG200745 and SAHA) and cell viability was determined by CCK-SK kit. Cell cycle analysis was performed using a flow cytometer. For western blotting of acetylation and apoptosis induction, antibodies to acetylated (on Lys 18) histone H3, histone H3, PARP, XIAP, caspases-3, –8, and –9, and actin were used. For measuring membrane potential of mitochondria, a flow cytometer was used after staining with TMRE. We established a murine leukemic model with infusing WEHI-3 leukemia cells in BALB/c mice, and tested anti-leukemic effects of HDIs in vivo. Lastly, we obtained leukemic cells from patients with AML and performed cell proliferation assay using CellTiter 96® Aqueous One Solution Reagent. Results: CG200745 and SAHA successfully inhibited HDAC activities in human leukemic cell lines. Both agents decreased cell viability in a dose-dependent manner and IC50 values were lower with CG200745 than with SAHA in all leukemic cell lines except one (KG-1). In U937 cell line, flow cytometry showed the accumulation of S population by both HDIs. Exposure of the cells to the HDIs resulted in activation of caspase-9 and –3, increase of PARP cleavage, and decrease of XIAP. Activation of caspase-8 was not noted. TMRE fluorescence levels decreased after treatment of HDIs in a dose-dependent manner and were correlated with decrease of XIAP and increase of apoptosis. Decrease of mitochondrial membrane potential was more prominent with CG200745 compared to SAHA. In both murine leukemic model using WEHI-3 leukemic cells and CellTiter assay using leukemic cells from AML patients, CG200745 showed more significant anti-leukemic activities than SAHA. Conclusion: CG200745 has significant anti-leukemic activities against AML cells and the effects appear to be mediated by activation of the intrinsic apoptotic pathway and induction of mitochondrial dysfunction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4666. doi:1538-7445.AM2012-4666
- Published
- 2012
36. Abstract 4518: Effects of a novel small molecule inhibitor of Wnt signal pathway, CWP232291, on primary tumor cells from patients with malignant hematologic diseases
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Je-Hwan Lee, Sung-Doo Kim, Jong Heun Lee, Jung-Hee Lee, Yunsuk Choi, Se-Woong Oh, Young-Hee Byun, Dae-Young Kim, Eun-Hye Hur, Sungsook Lee, Bon-Kwan Goo, Kyoo-Hyung Lee, and Kyung-Yun Jung
- Subjects
Cancer Research ,business.industry ,Daunorubicin ,Cancer ,Pharmacology ,medicine.disease ,Primary tumor ,Lymphoma ,medicine.anatomical_structure ,Oncology ,hemic and lymphatic diseases ,Cancer research ,Cytarabine ,Medicine ,Cytotoxic T cell ,Bone marrow ,business ,Multiple myeloma ,medicine.drug - Abstract
Background: Aberrant activation of Wnt signaling has been implicated in the pathogenesis of hematologic malignancies. CWP232291 is a novel small molecule that inhibits Wnt signaling through promotion of beta-catenin degradation. In vitro and in vivo anti-tumor activities of CWP232291 were demonstrated in previous studies using hematologic cancer cell lines (J.Y.C. 2010 AACR, LB-176). Here we report the effects of CWP232291 on primary tumor cells from patients with malignant hematologic diseases. Materials and methods: We performed cell viability assay using luminescent-based CellTiter Glo system to determine in vitro growth inhibitory activities in bone marrow mononuclear cells of healthy volunteers and in primary tumor cells collected from bone marrow of the patients with acute myeloid leukemia (AML) and B-cell neoplasms (B-cell non-Hodgkin lymphoma [B-NHL] and multiple myeloma [MM]). Western blot assay was done for changes of intracellular beta-catenin levels after the treatment of CWP232291. Summary of results: CWP232291 showed little effects on normal bone marrow cells, whereas it exerted potent cytotoxicities in a significant proportion of the patients’ samples (8 of 13 AML patients, 2 of 3 B-NHL patients, and 2 of 4 MM patients). The cytotoxic effects of CWP232291 at sub-micromolar levels were more potent than those of anti-leukemic cytotoxic agents such as cytarabine, daunorubicin, or doxorubicin. All of the tumor samples from the AML patients with t(8;21) (n=3), trisomy 8 (n=3), or MLL translocations (n=1) were sensitive to CWP232291. Baseline intracellular beta-catenin levels were elevated in both B-NHL patients’ samples that were sensitive to CWP232291 and the beta-catenin levels decreased after the treatment with CWP232291. Conclusion: Our data from primary patients’ samples provide a rationale for exploring the clinical activities of CWP232291 in the treatment of patients with hematologic malignancies, especially AML and B-cell neoplasms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4518. doi:10.1158/1538-7445.AM2011-4518
- Published
- 2011
37. Abstract 1245: Characterization of human leukemic cell lines and changes of the characteristics according to passage number
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Dae-Young Kim, Je-Hwan Lee, Sungsook Lee, Sung-Doo Kim, Eun-Hye Hur, Jung-Hee Lee, Kyoo-Hyung Lee, Bon-Kwan Goo, and Yunsuk Choi
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Cancer Research ,Mutation ,Matrigel ,HL60 ,Myeloid leukemia ,Biology ,biology.organism_classification ,medicine.disease_cause ,Molecular biology ,Jurkat cells ,chemistry.chemical_compound ,Nude mouse ,Oncology ,chemistry ,Cell culture ,medicine ,Protein kinase B - Abstract
Background: Human leukemic cell lines are valuable tools for the studies on the biology of hematologic cancers and new drug development. We investigated the baseline characteristics of human leukemic cell lines and changes of the properties according to passage number. Materials and methods: A total of 11 human leukemic cell lines were investigated in this study, including myeloid leukemia cell lines (HL60, NB4, Molm-13, MV4-11, KG-1, K562) and lymphoid leukemia cell lines (CCRFCEM, SR, U937, Molt4, Jurkat). Genetic mutations (N-Ras, K-Ras, B-Raf, FLT3-ITD, FLT3-TKD, MLL) and polymorphisms (MDR3435CT and GST genes [A, M, T]) were detected using appropriate methods such as PCR, RFLP or DNA sequencing. MDR activities were measured using Rhodamine 123 efflux assay. Establishment of xenograft model for each cell line was tried with subcutaneous injection of leukemic cells mixed with matrigel matrix into Balb/c nude mouse. Cell lines were maintained with two times of passage per week. Western blot assay was done for changes of expression of intracellular signaling pathway proteins such as ERK, p-ERK, AKT, p-AKT, and HR23B according to the passage number. Summary of results: N-Ras mutation was found in HL60 (Gln61Leu) and Molt4 (Gly13Val), K-Ras mutation in CCRFCEM (Gly12Asp) and NB4 (Ala18Asp), B-Raf mutation in none, FLT3-ITD and MLL rearrangements in Molm-13 and MV4-11, and FLT3-TKD in none. High MDR activity was noted in KG-1 (92.5%) and other cell lines showed less than 30% of MDR activities. Mouse xenograft model was established with 7 leukemic cell lines (HL60, NB4, MV4-11, Molm-13, K562, Molt4 and CCRFCEM). ERK phosphorylation was observed in most cell lines except CCRFCEM, but AKT phosphorylation was not found in any of the cell lines. As increasing the passage number, the levels of p-ERK in K562 and HL60 significantly decreased whereas those of p-AKT in Molm-13 were elevated. Conclusion: Our study results provide genetic and biologic data for human leukemic cell lines and show the importance of passage number of the leukemic cell lines in designing experiments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1245. doi:10.1158/1538-7445.AM2011-1245
- Published
- 2011
38. Genetic Alterations of Wilms' Tumor 1 (WT1) Gene In Korean Patients with Normal Karyotype Acute Myeloid Leukemia
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Miee Seoul, Yunsuk Choi, Sung-Nam Lim, Je-Hwan Lee, Young-Shin Lee, Dae-Young Kim, Young-Ah Kang, Eun-Hye Hur, Sung-Doo Kim, Kyoo-Hyung Lee, Mijin Jeon, and Jung-Hee Lee
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medicine.medical_specialty ,Mutation ,Immunology ,Induction chemotherapy ,Single-nucleotide polymorphism ,Wilms' tumor ,Cell Biology ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Gastroenterology ,Leukemia ,Internal medicine ,Genotype ,Gene duplication ,medicine ,Cancer research ,SNP - Abstract
Abstract 4852 Introduction: Acquired mutations of the WT1 gene have been reported in 5–10% of normal karyotype AML (NK-AML) patients. Poor prognostic impact of the mutations has been reported, but some studied found no such correlation. Recent report from Germany showed the association of single nucleotide polymorphism (SNP) rs16754 status with clinical outcomes in NK-AML (J Clin Oncol 2009; 28:578). We assessed clinical implication of WT1 gene alterations in Korean patients with NK-AML. Patients and Methods: This study included a total of 75 patients with NK-AML. All patients received standard induction chemotherapy (‘7+3’ regimen) at the Asan Medical Center, Seoul, Korea between May 1999 and Dec 2006. WT1 exons 7 and 9 were amplified using polymerase chain reaction (PCR) and purified PCR fragments were directly sequenced. The clinico-laboratory data were retrieved from the AMC Leukemia Registry. Results: WT1 mutations were found in four patients (5.3%): two duplication mutations and two insertion mutations. All mutations were in exon 7 and none in exon 9. Two of four patients harboring WT1 mutation failed to achieve complete remission (CR) and died at 3.9 and 7.0 months after diagnosis of AML. One of two patients attaining CR was alive without relapse at 44.0 month and another died in CR at 4.7 months. WT1 SNP rs16754 was AA genotype (WT1AA) in 5 (3.7%), AG (WT1AG) in 29 (38.2%), and GG (WT1GG) in 41 (54.7%). The findings are significantly different from those of German report (WT1AA in 74.3%, WT1AG in 24.1%, and WT1GG in 1.6%) (P Conclusion: The prognostic impact of WT1 mutation in NK-AML could not be assessed in this study due to low number of patients harboring the mutation, but three of four patients died with relatively short survival duration, suggesting poor prognosis of the patients with WT1 mutation. The frequency of WT1 SNPs rs16754 in our patients was different from that of German report and survivals were not significantly different according to the SNP genotypes. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
39. Abstract 5479: Glycogen synthase kinase-3 (GSK3) differently targets in MLL leukemia cells
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Je-Whan Lee, Eun-Hye Hur, Dae-Young Kim, and Mun-Jung Kang
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Cancer Research ,Cell growth ,Myeloid leukemia ,Biology ,medicine.disease ,Molecular biology ,Leukemia ,Histone H3 ,Histone ,Oncology ,Cell culture ,Acetylation ,GSK-3 ,hemic and lymphatic diseases ,medicine ,biology.protein - Abstract
Propose: We evaluated the anti-leukemic effect of GSK3 inhibitor for specific type of MLL-tranlocated cell line. Materials and methods: l GSK3 inhibitor: LiCl, SB216763, GSK3-IX l Cell line: MV4-11 [human lymphoblast, t(4:11)] MOLM-13 [human acute myeloid leukemia, ins(9:11)(q23;p22p23)] l Cell proliferation assay: XTT assay, Clonogenic assay l GSK3i activity & detection of histone acetylation and H3K4 methylation: Immunoblotting Summary: MLL gene encodes an enzyme which methylates histone H3 DNA-binding protein and positively regulates the expression of target genes in normal tissue. MLL rearrangement which is found in acute myeloid leukemia (AML), especially therapy-related AML, encodes fusion proteins that have lost H3 lys4-specific (H3K4) methyltransferase activity, and causes a transformation of hematopoietic cells into leukemia stem cells. GSK3, a serine/threonine kinase, plays a key role in glycogen metabolism and is constitutively expressed in resting cell. Although it has been thought that the inhibition of GSK3 causes apoptosis in neurons and other tissues, a paradoxical and unexpected cell death effect of GSK3 inhibition were reported recently in leukemic cell line with MLL translocation, especially t(4;11). Regarding the mechanism of the cytotoxic effect of GSK3 inhibitor, various molecules associated with the signaling pathway around MLL gene have been investigated. Acetylation of H3 peptides stimulates the activity of SET domain in MLL. MLL gene is cleaved at 2 conserved sites by taspase-1; N-terminal 320 kD fragment (N320) and a C-terminal 180 kD fragment (C180). RNA interference-mediated knockdown of taspase-1 resulted in an unprocessed MLL, and finally a loss of proper HOX gene expression. However, the exact mechanism has been still unknown and it remains to be uncertain whether GSK3 inhibitor shows cell death effect on various leukemic cell lines of MLL translocation with other partner gene. We intended to determine whether the inhibition of GSK3 induced cell death in different types of leukemia cell lines with MLL translocation. We examined the apoptotic effects of GSK3 inhibitors on MV4-11 and MOLM-13 cell line. LiCl and GSK3-IX induced cell death, H3K4 methylation and histone acetylation in dose-dependent manners on MV4-11 but did not induce on MOLM-13. However, SB216763 did not induced cell death both cell lines. Conclusion: Cell death effects with the inhibition of GSK3 may be different among leukemic cell line with MLL translocation according to the partner gene of MLL translocation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5479.
- Published
- 2010
40. Influence of Glutathione S-Transferase (GST) Gene Polymorphisms On the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation
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Dae-Young Kim, Hyeong-Seok Lim, Seong-Gil Ryu, Kyoo-Hyung Lee, Jung-Hee Lee, Sung-Cheol Yun, Sung-Doo Kim, Kyun-Seop Bae, Young-Ah Kang, Gyu-Jeong Noh, Je-Hwan Lee, Eun-Hye Hur, Sang Beom Han, M. Kang, Sung-Nam Lim, and Young-Shin Lee
- Subjects
medicine.medical_specialty ,Univariate analysis ,biology ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,Biochemistry ,Confidence interval ,Transplantation ,Endocrinology ,Glutathione S-transferase ,Pharmacokinetics ,Internal medicine ,Genotype ,medicine ,biology.protein ,Gene polymorphism ,Busulfan ,medicine.drug - Abstract
Abstract 1179 Poster Board I-201 Introduction: Intravenous (iv) busulfan can yield a more consistent dosing and pharmacokinetic profile than oral formulation, but there is still inter-patient variability in systemic exposure with iv busulfan. GST gene polymorphisms may explain the variability because busulfan is metabolized in liver through conjugation with GST family. Thus, we investigated the influence of polymorphisms of 3 GST genes, GSTA1, GSTM1, and GSTT1 on the clearance of iv busulfan in adult patients undergoing hematopoietic cell transplantation (HCT). Patients and Methods: We analyzed the PK data from 60 patients, who were included in a randomized trial of 4-times-daily (0.8 mg/kg q 6 h) versus once-daily (3.2 mg/kg once a day) iv busulfan in a conditioning therapy for HCT (Biol Blood Marrow Transplant 2007;13:1095). Limited sampling strategy was used for PK studies, which were performed for the first busulfan dosing using a validated LC with tandem MS. Busulfan plasma clearance (CL) was derived from 1 compartment model. GSTA1 was genotyped by PCR followed by RFLP, and GSTM1- and GSTT1-null genotypes were identified by PCR procedure. Results: GSTA1 genotyping revealed GSTA1*A/*A in 46 patients (77%) and GSTA1*A/*B in 14 (23%). GSTM1-null genotype was found in 25 patients (43%) and GSTT1-null genotype in 34 (59%). Each polymorphism of GST genes was not associated with sex or age of the patients. In univariate analysis, clearance (CL, mL/min/kg) of iv busulfan was significantly associated with GSTA1 polymorphisms (*A/*A vs. *A/*B, 2.036 ± 0.340 vs. 1.789 ± 0.295, P=0.017), but not with GSTM1 (present vs. null, 2.012 ± 0.390 vs. 1.915 ± 0.279, P=0.274) or GSTT1 (present vs. null, 2.047 ± 0.286 vs. 1.917 ± 0.380, P=0.064) polymorphisms. Actual body weight in kilogram was also significantly associated with CL of iv busulfan (Pearson's correlation coefficient, -0.420; P=0.001). Linear regression analysis demonstrated that GSTA1 gene polymorphism (regression coefficient, -0.255; 95% CI, -0.440 to -0.071; P=0.008) and actual body weight (regression coefficient, -0.012; 95% CI, -0.091 to -0.005; P=0.001) were independently significant factors for CL of iv busulfan. Null genotype of GSTM1 and/or GSTT1, although each polymorphism was not a significant factor, showed decreased clearance of iv busulfan both in patients with GSTA1 *A/*A and those with GSTA1 *A/*B (Figure 1). The CL was similar between in patients with GSTA1 *A/*A with null genotype of both GSTM1 and GSTT1 and in those with GSTA1 *A/*B with present genotype of both GSTM1 and GSTT1. Conclusion: GSTA1 gene polymorphism was an important determining factor for the clearance of iv busulfan. Polymorphisms of GSTM1 and GSTT1 genes also appeared to have a supplementary role in the pharmacokinetics of iv busulfan. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2009
41. C3435T Polymorphism of MDR1 Gene Is Not Associated with p-Glycoprotein Function of Leukemic Blasts and Clinical Outcomes in Patients with Acute Myeloid Leukemia
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Seong-Gil Ryu, Jung-Hee Lee, Ip-Sol Kang, Miee Seol, Chan-Jeoung Park, Young-Ah Kang, Hee-Jung Lee, Seong-Jun Choi, Eun-Hye Hur, Keun-Hee Kim, Hyung-Sook Chi, Kyung-Soo Shim, Kyoo-Hyung Lee, Michael Jinpyo Lee, Je-Hwan Lee, and Young-Shin Lee
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medicine.medical_specialty ,business.industry ,Immunology ,Induction chemotherapy ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,law.invention ,Genotype frequency ,Leukemia ,medicine.anatomical_structure ,law ,Internal medicine ,Genotype ,medicine ,Bone marrow ,Restriction fragment length polymorphism ,business ,Polymerase chain reaction - Abstract
P-glycoprotein (P-gp) function of leukemic blasts is associated with chemotherapy resistance in acute myeloid leukemia (AML). The C3435T polymorphism in the human MDR1 gene has been studied in AML and contradictory results were reported regarding clinical implications of the polymorphism. We investigated the association of C3435T polymorphism of MDR1 gene with P-gp function of leukemic blasts and clinical outcomes in patients with AML excluding M3 subtype. A total of 200 patients, 127 males and 73 females, were included in this study. Median age was 44 years (range, 14–75). All patients were newly diagnosed and were treated with standard ‘7+3’ induction chemotherapy regimens at the Asan Medical Center, Seoul, Korea between May 1999 and November 2006. The C3435T polymorphism was analyzed with PCR/RFLP method. P-gp function of leukemic blasts was measured at diagnosis by the rhodamine-123 efflux assay. The clinico-laboratory data at diagnosis and data on clinical outcomes were obtained from the AMC Leukemia Registry. Genotype frequency of C3435T polymorphism was 71 (35.5%) for CC, 93 (46.5%) for CT, and 36 (18.0%) for TT. There were no significant differences between different genotypes of C3435T polymorphism regarding age, sex, FAB subtypes, initial leukocyte counts, percentages of blasts in bone marrow or blood at diagnosis, and cytogenetic risk groups. P-gp function of leukemic blasts was not significantly different according to the genotype of C3435T polymorphism: 32.2 ± 24.0% for CC, 35.8 ± 21.4% for CT, and 29.1 ± 24.0% for TT (P=0.370). Complete remission was induced in 79.2% for CC, 79.8% for CT, and 77.8% for TT (P=0.969). Overall, relapse-free and event-free survival probabilities at 5 years were 47.6%, 55.4% and 51.0% for CC, 51.3%, 51.0% and 42.5% for CT, and 53.1%, 60.0% and 55.0% for TT (P= 0.594, 0.932 and 0.764, respectively). In conclusion, C3435T polymorphism does not have significant clinical implications in AML regarding P-gp function of leukemic blasts and clinical outcomes.
- Published
- 2007
42. Randomized Comparison of 4-Times-Daily Versus Once-Daily Intravenous Busulfan in a Conditioning Therapy for Hematopoietic Cell Transplantation (HCT)
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Je-Hwan Lee, Seong-Gil Ryu, Miee Seol, Jung-Hee Lee, Kyoo Hyung Lee, Kyun-Seop Bae, Gyu-Jeong Noh, Young-Shin Lee, Soo Han Lee, Moo-Song Lee, Sang Beom Han, Eun-Hye Hur, Sung-Cheol Yun, and Seong-Jun Choi
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medicine.medical_specialty ,Hepatic veno-occlusive disease ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,law.invention ,Transplantation ,Regimen ,Pharmacokinetics ,Randomized controlled trial ,law ,Anesthesia ,Internal medicine ,medicine ,Cumulative incidence ,Dosing ,business ,Busulfan ,medicine.drug - Abstract
Several single-arm studies have shown that once-daily or twice-daily intravenous busulfan (iBU) may be equally safe and effective compared to traditional 4-times-daily iBU. We performed a prospective randomized trial of 4-times-daily vs. once-daily dosing of iBU in a conditioning therapy for HCT, and compared pharmacokinetic (PK) characteristics of iBU and clinical outcomes in terms of engraftment, post-HCT toxicities, non-relapse mortality (NRM), and overall survival. All of 60 patients, who received iBU on the first day of conditioning therapy for HCT, were randomized to receive iBU either as 0.8 mg/kg over 2 hr 4 times a day (BU4 arm) or 3.2 mg/kg over 3 hr once a day (BU1 arm) between May 2004 and August 2005. Limited sampling strategy was used for PK studies, which were done for the first busulfan dosing. Baseline patient and donor characteristics were well balanced between 2 arms regarding sex, age, diagnosis of underlying disease, time from diagnosis to HCT, disease status at HCT, GVHD prophylaxis regimen, conditioning therapy regimen, ABO mismatch between donor and recipient, donor-recipient sex pair, donor age, type of graft, donor type, and cell doses of graft. The complete PK data were obtained from all 60 patients and those were comparable between 2 arms: elimination half-life (mean ± SD) was 2.75 ± 0.22 vs. 2.83 ± 0.21 hr in BU4 arm vs. BU1 arm, respectively (P=0.304), estimated AUC was 7933.43 ± 2177.71 vs. 8556.86 ± 2452.07 μM × min per day (P=0.367), and clearance was 2.05 ± 0.36 vs. 1.91 ± 0.31 ml/min/kg (P=0.133). Median times to engraftment of neutrophils (BU4 arm vs. BU1 arm, 14 vs. 14 days, P=872) and platelets (26.5 vs. 25.5 days, P=0.946) after HCT were similar between 2 arms. There were no significant differences in cumulative incidence of acute GVHD (BU4 arm vs. BU1 arm, 31.0% vs. 13.8%, P=0.145) and occurrence of CMV infection (40.0% vs. 23.3%, P=0.165) or hepatic veno-occlusive disease (10.0% vs. 16.7%, P=0.448). Other toxicities within 100 days after HCT were not significantly different between two arms. Cumulative incidence of NRM was 25.5% vs. 17.3% (P=0.488) and overall survival probability at 1 year was 69.0% vs. 70.0% (P=0.758). In conclusion, our randomized study demonstrates that once-daily iBU has similar PK profiles and results in at least not inferior clinical outcomes compared to traditional 4-times-daily iBU.
- Published
- 2006
43. Randomized Comparison of Four-Times-Daily versus Once-Daily Intravenous Busulfan in Conditioning Therapy for Hematopoietic Cell Transplantation
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Miee Seol, Sung-Cheol Yun, Seong-Jun Choi, Kyoo-Hyung Lee, Je-Hwan Lee, Sang Beom Han, Seong-Gil Ryu, Young-Shin Lee, Moo-Song Lee, Kyun-Seop Bae, Soo Han Lee, Jung-Hee Lee, Eun-Hye Hur, and Gyu-Jeong Noh
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Adult ,Male ,Hepatic veno-occlusive disease ,Transplantation Conditioning ,Adolescent ,Hepatic Veno-Occlusive Disease ,Graft vs Host Disease ,Drug Administration Schedule ,Conditioning therapy ,law.invention ,Randomized controlled trial ,Pharmacokinetics ,law ,medicine ,Humans ,Cumulative incidence ,Survival rate ,Busulfan ,Transplantation ,Hematopoietic cell transplantation ,business.industry ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Intravenous busulfan ,Hematology ,Middle Aged ,medicine.disease ,Once-daily administration ,Survival Rate ,Anesthesia ,Conditioning ,Female ,business ,medicine.drug - Abstract
Sixty patients were randomized to receive intravenous busulfan (iBU) either as 0.8 mg/kg, over 2 hours 4 times a day (BU4 arm) or 3.2 mg/kg, over 3 hours once a day (BU1 arm) in conditioning therapy for hematopoietic cell transplantation. The complete pharmacokinetic parameters for the first busulfan dose were obtained from all patients and were comparable between the 2 arms: for the BU4 and BU1 groups, elimination half-life (mean ± SD) was 2.75 ± 0.22 versus 2.83 ± 0.21 hours, estimated daily AUC was 6058.0 ± 1091.9 versus 6475.5 ± 1099.4 μM·min per day, and clearance was 2.05 ± 0.36 versus 1.91 ± 0.31 mL/min/kg, respectively. Times to engraftment after transplantation were similar between the 2 arms. No significant differences were evident in the occurrence of acute graft-versus-host disease (aGVHD) and hepatic veno-occlusion disease (VOD). Moreover, other toxicities observed within 100 days after transplantation were not significantly different between the 2 arms. The cumulative incidence of nonrelapse mortality was 20.8% in BU4 arm and 13.3% in BU1 arm. In conclusion, our randomized study demonstrates that the pharmacokinetic profiles and posttransplant complications are similar for once-daily iBU and traditional 4-times-daily iBU.
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44. Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation
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Jung-Hee Lee, Yunsuk Choi, Eun-Hye Hur, Sang Beom Han, Gyu-Jeong Noh, Sung Cheol Yun, Dae-Young Kim, Je-Hwan Lee, Sung-Doo Kim, Hyeong Seok Lim, Kyoo Hyung Lee, Kyun-Seop Bae, and Sung Nam Lim
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Adult ,Male ,Alkylating Agents ,Transplantation Conditioning ,Adolescent ,Pharmacology ,Drug Administration Schedule ,Young Adult ,Pharmacokinetics ,Polymorphism (computer science) ,Genotype ,medicine ,Humans ,Infusions, Intravenous ,Cyclophosphamide ,Busulfan ,Glutathione Transferase ,Transplantation ,Polymorphism, Genetic ,Hematopoietic cell transplantation ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Isoenzymes ,Glutathione S-transferase ,Pharmacogenetics ,Hematologic Neoplasms ,biology.protein ,Female ,Gene polymorphism ,business ,Vidarabine ,medicine.drug ,Glutathione S-Transferase - Abstract
Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes (GSTA1, GSTM1, and GSTT1) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B (P = .004), GSTM1/GSTT1 double-null genotype (P = .039), and actual body weight (P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1- and GSTT-null genotypes, showed a significant correlation between GST genotype and busulfan clearance (P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.
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45. Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia.
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Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, and Lee KH
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- Adult, Cytarabine administration & dosage, Daunorubicin administration & dosage, Dose-Response Relationship, Drug, Female, Humans, Idarubicin administration & dosage, Induction Chemotherapy, Male, Middle Aged, Prognosis, Prospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose We compared two induction regimens, idarubicin (12 mg/m
2 /d for 3 days) versus high-dose daunorubicin (90 mg/m2 /d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2 /d for 7 days). Results Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event-free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028). Conclusion This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.- Published
- 2017
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