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Article: The Pathologic and Genetic Characteristics of Extranodal NK/T-Cell Lymphoma.

Kim, Hyunsung / Ko, Young Hyeh

2022 Volume 12, Issue 1

Abstract: Extranodal NK/T-cell lymphoma is a neoplasm of NK cells or cytotoxic T cells presenting in extranodal sites, most often in the nasal cavity. The typical immunophenotypes are cCD3+, sCD3-, CD4-, CD5-, CD8-, CD16-, and CD56+ with the expression of ... ...

Abstract	Extranodal NK/T-cell lymphoma is a neoplasm of NK cells or cytotoxic T cells presenting in extranodal sites, most often in the nasal cavity. The typical immunophenotypes are cCD3+, sCD3-, CD4-, CD5-, CD8-, CD16-, and CD56+ with the expression of cytotoxic molecules. Tumor subsets express NK cell receptors, CD95/CD95L, CD30, MYC, and PDL1. Virtually all the tumor cells harbor the EBV genome, which plays a key role in lymphomagenesis as an epigenetic driver. EBV-encoded oncoproteins modulate the host-cell epigenetic machinery, reprogramming the viral and host epigenomes using host epigenetic modifiers. NGS analysis revealed the mutational landscape of ENKTL, predominantly involving the JAK-STAT pathway, epigenetic modifications, the RNA helicase family, the RAS/MAP kinase pathway, and tumor suppressors, which indicate an important role of these pathways and this group of genes in the lymphomagenesis of ENKTL. Recently, three molecular subtypes were proposed, the tumor-suppressor/immune-modulator (TSIM), MGA-BRDT (MB), and HDAC9-EP300-ARID1A (HEA) subtypes, and they are well-correlated with the cell of origin, EBV pattern, genomic alterations, and clinical outcomes. A future investigation into the function and interaction of discovered genes would be very helpful for better understanding the molecular pathogenesis of ENKTL and establishing better treatment strategies.
Language	English
Publishing date	2022-01-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life12010073
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Article ; Online: EBV and human cancer.

Ko, Young-Hyeh

Experimental & molecular medicine

2015 Volume 47, Page(s) e130

MeSH term(s)	Epstein-Barr Virus Infections/complications ; Herpesvirus 4, Human/physiology ; Humans ; Neoplasms/etiology
Language	English
Publishing date	2015-01-23
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ZDB-ID	1328915-9
ISSN	2092-6413 ; 1226-3613 ; 0378-8512
ISSN (online)	2092-6413
ISSN	1226-3613 ; 0378-8512
DOI	10.1038/emm.2014.109
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Article ; Online: SLAMF1 contributes to cell survival through the AKT signaling pathway in Farage cells.

Yoon, Heejei / Kim, Eung Kweon / Ko, Young Hyeh

PloS one

2020 Volume 15, Issue 9, Page(s) e0238791

Abstract: SLAMF1 is often overexpressed in Epstein Barr virus (EBV)-infected B cell tumors. However, its role in the pathogenesis of EBV-infected B cell tumors remains largely unknown. Here, we generated SLAMF1-deficient EBV+ tumor cells and examined the effect of ...

Abstract	SLAMF1 is often overexpressed in Epstein Barr virus (EBV)-infected B cell tumors. However, its role in the pathogenesis of EBV-infected B cell tumors remains largely unknown. Here, we generated SLAMF1-deficient EBV+ tumor cells and examined the effect of its deficiency on cell proliferation and cell survival. There were no significant differences in cell proliferation and cell cycle distribution for short periods between the SLAMF1-deficient and wild-type cells. However, the deficient cells were more resistant to an AKT inhibitor (MK-2206). When the both cells were co-cultured and repeatedly exposed to the limitations in nutrition and growth factors, the SLAMF1-deficient cells were gradually decreased. We observed that levels of phospho-AKT were differentially regulated according to the nutritional status between the SLAMF1-deficient and wild-type cells. A decrease in phospho-AKT was observed in SLAMF1-deficient cells as well as an increase in pro-apoptotic Bim just before cell passage, which may have been due to the loss of SLAMF1 under poor growth condition. Overall, SLAMF1 is not a strong survival factor, but it seems to be necessary for cell survival in unfavorable growth condition.
MeSH term(s)	B-Lymphocytes/metabolism ; Cell Survival ; Herpesvirus 4, Human/metabolism ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Signaling Lymphocytic Activation Molecule Family Member 1/metabolism ; Tumor Cells, Cultured
Chemical Substances	Signaling Lymphocytic Activation Molecule Family Member 1 (169535-43-7) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2020-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0238791
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Article: Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma.

Choi, Sung Yong / Choi, Jaehyuck / Hwang, Inwoo / Cho, Junhun / Ko, Young-Hyeh / Jeong, Han-Sin

Journal of clinical medicine

2022 Volume 11, Issue 7

Abstract: Background: Recurrence in pleomorphic adenoma (PA) has been debated as a risk factor for malignant transformation (MT). In this study, we investigated whether recurrence is a risk factor for MT, by longitudinally analyzing cases with recurrent PA (RPA), ... ...

Abstract	Background: Recurrence in pleomorphic adenoma (PA) has been debated as a risk factor for malignant transformation (MT). In this study, we investigated whether recurrence is a risk factor for MT, by longitudinally analyzing cases with recurrent PA (RPA), and carcinomas from PA (CXPA) or RPA (CXRPA). Methods: The study population included 24 CXPA, 24 RPA, 6 CXRPA, and 386 PA cases (study period 2010−2018). Time and event data were collected from the medical documents to identify the time−event sequences. Results: The time interval to MT in CXRPA was significant longer than that of benign recurrence (median 342.0 vs. 109.5 months). In CXRPA, the recurrence intervals were not shorter than those in RPA according to recurrence frequency. Crudely, the MT rate was 5.9% among primary cases and 20.0% among recurrent cases. However, the time-adjusted MT rates increased up to 11.4% (incubation time > 60 months) and 20.0% (>120 months) in primary cases, which were not different from recurrent cases. Conclusion: In these longitudinal analyses, we did not find any clinical evidence that recurrence facilitates MT in the background of PA. Instead, a long incubation time seems to be a key factor for MT of underlying RPA.
Language	English
Publishing date	2022-03-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11071808
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Article ; Online: CD47 overexpression is common in intestinal non-GCB type diffuse large B-cell lymphoma and associated with 18q21 gain.

Cho, Junhun / Yoon, Sang Eun / Kim, Seok Jin / Ko, Young Hyeh / Kim, Won Seog

Blood advances

2022

Abstract: The CD47/SIRPα pathway is an emerging immune checkpoint that is a new therapeutic target. We investigated CD47 expression in DLBCL of various subtypes and organs. Moreover, the relationship between CD47 expression and genetic alterations was analyzed ... ...

Abstract	The CD47/SIRPα pathway is an emerging immune checkpoint that is a new therapeutic target. We investigated CD47 expression in DLBCL of various subtypes and organs. Moreover, the relationship between CD47 expression and genetic alterations was analyzed using panel-based massively parallel sequencing (NGS). CD8, CD68, and CD47 immunohistochemical staining were performed on 238 DLBCL patients. CD47 was scored according to intensity on a 5-level scale, and CD8 and CD68 were quantitatively evaluated using QuPath software. Panel based NGS was performed in 37 patients. In CD8 and CD68 quantitative analyses by organs, intestinal DLBCL showed significantly lower cytotoxic T-cell infiltration than that in others (P<0.001). The CD47-high group comprised 24 of 58 (41.4%) in DLBCL from intestine and 15 of 180 (8.3%) in DLBCL from other organs (P<0.001). The 18q21 gain/amplification was found in 10 of 37 patients, and all of them were CD47-high. Intestinal CD47-high DLBCL occurred in terminal ileum to ascending colon, and was restricted to non-germinal center B-cell type. In the survival analyses, the prognosis of non-intestinal CD47-high DLBCL was poorer than that of intestinal CD47-high DLBCL (P=0.025). CD47-high DLBCL was closely associated with 18q21 gain/amplification and showed a high prevalence in intestine. We propose to classify CD47-high DLBCL into intestinal and non-intestinal type. Further studies are necessary to assess whether the constellation of features seen here is reproducible and sufficient to consider primary intestinal DLBCL as a distinct biological entity.
Language	English
Publishing date	2022-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021006305
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Article ; Online: LMP1+SLAMF1high cells are associated with drug resistance in Epstein-Barr virus-positive Farage cells.

Yoon, Heejei / Ko, Young Hyeh

Oncotarget

2017 Volume 8, Issue 15, Page(s) 24621–24634

Abstract: How Epstein-Barr virus (EBV) affects the clinical outcome of EBV-positive diffuse large B-cell lymphoma (DLBCL) remains largely unknown. The viral oncogene LMP1 is at the crux of tumorigenesis and cell survival. Therefore, we examined the association ... ...

Abstract	How Epstein-Barr virus (EBV) affects the clinical outcome of EBV-positive diffuse large B-cell lymphoma (DLBCL) remains largely unknown. The viral oncogene LMP1 is at the crux of tumorigenesis and cell survival. Therefore, we examined the association between LMP1high cells drug resistance. We first assessed SLAMF1 as a surrogate marker for LMP1high cells. LMP1 and its target gene CCL22 were highly expressed in SLAMF1high Farage cells. These cells survived longer following treatment with a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Genes associated with interferon-alpha, allograft rejection, NF-κB and STAT3 were also overexpressed in the surviving Farage cells. Specifically, CHOP treatment increased IL10, LMP1 and pSTAT3 expression levels in a dose-dependent fashion. Addition of exogenous IL4 greatly increased the levels of LMP1 and pSTAT3, which rendered the Farage cells more resistant to CHOP by up-regulating the anti-apoptotic genes BCL-XL and MCL1. The Farage cells were sensitive to Velcade and STAT3, 5, and 6 inhibitors. Inhibition of NF-κB and STAT3, in combination with CHOP, decreased LMP1 levels and effectively induced cell death in the Farage cells. We suggest that LMP1high cells are responsible for the poor drug response of EBV+ DLBCL and that perturbation of the NF-κB and STAT signaling pathways increases toxicity in these cells.
Language	English
Publishing date	2017-04-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.15600
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Article: A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma.

Lee, Yong-Pyo / Jung, Ye Ji / Cho, Junhun / Ko, Young Hyeh / Kim, Won Seog / Kim, Seok Jin / Yoon, Sang Eun

Blood research

2023 Volume 58, Issue 4, Page(s) 208–220

Abstract: Background: While treatment strategies for mantle cell lymphoma (MCL) have evolved, patients often experience disease progression and require additional treatment therapies. Ibrutinib presents a promising option for relapsed or refractory MCL (RR-MCL). ... ...

Abstract	Background: While treatment strategies for mantle cell lymphoma (MCL) have evolved, patients often experience disease progression and require additional treatment therapies. Ibrutinib presents a promising option for relapsed or refractory MCL (RR-MCL). This study investigated real-world treatment outcomes of ibrutinib in patients with RR-MCL. Methods: A single-center retrospective analysis investigated clinical characteristics and survival outcomes of patients with RR-MCL, treated with ibrutinib. Results: Forty-two patients were included, with 16 received rituximab and bendamustine, and 26 receiving anthracycline-based regimens as front-line treatment. During a median follow-up of 46.0 months, the response rate to ibrutinib was 69%, with 12 CRs and 8 partial responses. Disease progression (54.8%) and adverse events (11.9%) were the primary reasons for discontinuation. Median progression-free survival (PFS) and overall survival (OS) were approximately 16.4 and 50.1 months, respectively. Patients older than 70 years ( Conclusion: This study underscores the importance of considering patient characteristics before administering ibrutinib as salvage therapy. Early relapse was associated with poor outcomes, highlighting the need for novel therapeutic strategies.
Language	English
Publishing date	2023-11-05
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2711910-5
ISSN	2288-0011 ; 2287-979X
ISSN (online)	2288-0011
ISSN	2287-979X
DOI	10.5045/br.2023.2023208
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Article: Real-World Data Analysis of Survival Outcomes and Central Nervous System Relapses in Testicular Diffuse Large B Cell Lymphoma.

Lee, Yong-Pyo / Yoon, Sang Eun / Cho, Junhun / Ko, Young Hyeh / Oh, Dongryul / Ahn, Yong Chan / Kim, Won Seog / Kim, Seok Jin

Cancer management and research

2023 Volume 15, Page(s) 463–474

Abstract: Background: Primary testicular lymphoma is a rare type of non-Hodgkin lymphoma, mostly of the diffuse large B cell lymphoma (DLBCL). Although a consensus on standard treatment has been established, unresolved issues remain, such as recurrence in the ... ...

Abstract	Background: Primary testicular lymphoma is a rare type of non-Hodgkin lymphoma, mostly of the diffuse large B cell lymphoma (DLBCL). Although a consensus on standard treatment has been established, unresolved issues remain, such as recurrence in the central nervous system (CNS). Methods: We retrospectively analyzed the clinical characteristics and survival outcomes of 65 testicular DLBCL patients according to clinical settings and treatment modalities. Results: The median age of the patients in our study was 65 years, and two-thirds of them had disease limited to one testis. There was no right or left lateralization of testicular involvement. Over a median follow-up of 53.9 months (95% confidence interval 34.0-73.7 months), patients with stage I disease and a low international prognostic index score showed better survival outcomes than those in other categories. Orchiectomy, six cycles of chemotherapy, and radiation therapy (RT) to the contralateral testis demonstrated survival benefits, whereas CNS prophylaxis therapy did not reduce CNS recurrence. During the follow-up period, the survival curves showed continuous decline, mostly due to disease progression. CNS recurrence was observed in 15% of patients, and parenchymal involvement was dominant. However, no factors were associated with CNS recurrence in our analyses. Although our molecular analyses were performed in a small number of patients, Conclusion: In our study, treatment with orchiectomy, six cycles of immunochemotherapy, and contralateral RT was effective. However, because CNS prophylaxis is an essential part of testicular DLBCL management, better treatment strategies than intrathecal therapy are required.
Language	English
Publishing date	2023-06-05
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2508013-1
ISSN	1179-1322
ISSN	1179-1322
DOI	10.2147/CMAR.S407837
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Article ; Online: Clinicopathological and molecular genetic characteristics of primary gastric follicular lymphoma.

Kim, Hyunsung / Shin, Donghoon / Son, Seng-Myoung / Cho, Junhun / Kim, Ji Eun / Kim, Yeseul / Jeon, Taesung / Ko, Young Hyeh

Human pathology

2023 Volume 136, Page(s) 114–122

Abstract: Primary gastric follicular lymphomas (FLs) have been rarely reported, and little is known about their characteristics. In the present study, we report 5 cases of primary gastric FL and describe their clinicopathological and molecular genetic features. A ... ...

Abstract	Primary gastric follicular lymphomas (FLs) have been rarely reported, and little is known about their characteristics. In the present study, we report 5 cases of primary gastric FL and describe their clinicopathological and molecular genetic features. A total of 7 samples from 5 patients were investigated for clinicopathological characteristics and somatic mutations by the targeted sequencing of 50 lymphoma-related genes. Two cases were identified as slightly elevated submucosal tumors and 3 cases as polypoid tumors. Histologically, all cases were low-grade FLs. The immunoprofile was CD20
MeSH term(s)	Humans ; Lymphoma, Follicular/genetics ; Lymphoma, Follicular/therapy ; Lymphoma, Follicular/metabolism ; In Situ Hybridization, Fluorescence ; Janus Kinases/genetics ; Janus Kinases/metabolism ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Signal Transduction ; Neoplasm Recurrence, Local/genetics ; Proto-Oncogene Proteins c-bcl-2/genetics ; Molecular Biology ; Translocation, Genetic
Chemical Substances	Janus Kinases (EC 2.7.10.2) ; STAT Transcription Factors ; Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2023-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207657-3
ISSN	1532-8392 ; 0046-8177
ISSN (online)	1532-8392
ISSN	0046-8177
DOI	10.1016/j.humpath.2023.04.007
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Article ; Online: Chronic active EBV infection: the experience of the Samsung Medical Center in South Korea.

Lee, Tae-Hee / Ko, Young-Hyeh

Boletin medico del Hospital Infantil de Mexico

2016 Volume 73, Issue 1, Page(s) 10–17

Abstract: Background: Chronic active EBV infection (CAEBV) of T-cell or NK-cell type is an EBV+ polyclonal, oligoclonal or often monoclonal lymphoproliferative disorder (LPD) recognized as representing the spectrum of EBV-associated T-cell and NK-cell LPD with ... ...

Abstract	Background: Chronic active EBV infection (CAEBV) of T-cell or NK-cell type is an EBV+ polyclonal, oligoclonal or often monoclonal lymphoproliferative disorder (LPD) recognized as representing the spectrum of EBV-associated T-cell and NK-cell LPD with different clinical presentations; one systemic and two cutaneous disorders including hydroa vacciniforme-like T-cell LPD and mosquito bite hypersensitivity. The systemic form of the disease is characterized by fever, persistent hepatitis, hepatosplenomegaly and lymphadenopathy, which shows varying degrees of clinical severity depending on the immune response of the host and the EBV viral load. Case reports: We described the clinicopathological findings of two children with CAEBV with a brief review of the literature. Conclusions: Recognition of the disease is important for adequate management of the patient. EBV analysis should be included in the principal diagnostic tests for febrile children.
Language	English
Publishing date	2016-01
Publishing country	Mexico
Document type	Journal Article
ZDB-ID	730519-9
ISSN	1665-1146 ; 1665-1146 ; 0539-6115 ; 0539-6123
ISSN (online)	1665-1146
ISSN	1665-1146 ; 0539-6115 ; 0539-6123
DOI	10.1016/j.bmhimx.2015.12.003
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