Cancer Research and Treatment

Original Articles

EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-Barr Virus Associated Chronic Lymphocytic Leukemia: Dan-Min Xu, Yi-Lin Kong, Li Wang, Hua-Yuan Zhu, Jia-Zhu Wu, Yi Xia, Yue Li, Shu-Chao Qin, Lei Fan, Jian-Yong Li, Jin-Hua Liang, Wei Xu; Cancer Res Treat. 2020;52(2):492-504. Published online October 29, 2019; DOI: https://doi.org/10.4143/crt.2019.457

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Purpose
The purpose of this study was to investigate the prognostic impact of Epstein-Barr virus (EBV)–microRNA (miRNA, miR)-BHRF1-1 with chronic lymphocytic leukemia (CLL) as well as role of EBV-miR-BHRF1-1 in p53 gene.
Materials and Methods
Quantitative reverse transcription–polymerase chain reaction and western blotting were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL.
Results
p53 aberration was associated with the higher expression level of EBV-miR-BHRF1-1 (p < 0.001) which was also an independent prognostic marker for overall survival (p=0.028; hazard ratio, 5.335; 95% confidence interval, 1.193 to 23.846) in 97 newly-diagnosed CLL patients after adjusted with International Prognostic Index for patients with CLL. We identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3′- untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1- 1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines.
Conclusion
This study supported the role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

Citations

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A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection
Seyedeh Zahra Bahojb Mahdavi, Asiyeh Jebelli, Parisa Shiri Aghbash, Behzad Baradaran, Mohammad Amini, Fatemeh Oroojalian, Nasser Pouladi, Hossein Bannazadeh Baghi, Miguel de la Guardia, Amir Ali Mokhtarzadeh
Medicinal Research Reviews.2025; 45(2): 349. CrossRef
USP7 Inhibitors Destabilize EBNA1 and Suppress Epstein‐Barr Virus Tumorigenesis
Christopher Chen, Kush Addepalli, Samantha S. Soldan, Leonardo Josue Castro‐ Munoz, Sarah Preston‐Alp, Rishi J. Patel, Coltin J. Albitz, Hsin‐Yao Tang, Italo Tempera, Paul M. Lieberman
Journal of Medical Virology.2025;[Epub] CrossRef
The critical role of ferroptosis in virus-associated hematologic malignancies and its potential value in antiviral-antitumor therapy
Miao Miao, Yuelei Chen, Xuehan Wang, Shengyang Li, Rong Hu
Virulence.2025;[Epub] CrossRef
Longitudinal analysis of the impact of rituximab on circulating EBV miRNAs in three paediatric kidney transplant recipients
Jaythoon Hassan, Gabriel Gonzalez, Maria Stack, Niamh Dolan, Clodagh Sweeney, Cillian De Gascun, Jeff Connell, Atif Awan, Michael Riordan
Journal of Clinical Virology Plus.2024; 4(1): 100171. CrossRef
Epstein-Barr virus deubiquitinating enzyme BPLF1 is involved in EBV carcinogenesis by affecting cellular genomic stability
Hantao Wu, Bo-Wei Han, Tiancai Liu, Min Zhang, Yingsong Wu, Jing Nie
Neoplasia.2024; 55: 101012. CrossRef
The Emerging Role of Ferroptosis in EBV-Associated Cancer: Implications for Cancer Therapy
Shan He, Cheng Luo, Feng Shi, Jianhua Zhou, Li Shang
Biology.2024; 13(7): 543. CrossRef
From virus to cancer: Epstein–Barr virus miRNA connection in Burkitt's lymphoma
Shahram Jalilian, Mohammad-Navid Bastani
Infectious Agents and Cancer.2024;[Epub] CrossRef
MicroRNAs: Small but Key Players in Viral Infections and Immune Responses to Viral Pathogens
Anais N. Bauer, Niska Majumdar, Frank Williams, Smit Rajput, Lok R. Pokhrel, Paul P. Cook, Shaw M. Akula
Biology.2023; 12(10): 1334. CrossRef
Viral Encoded miRNAs in Tumorigenesis: Theranostic Opportunities in Precision Oncology
Rodney Hull, Rahaba Marima, Mohammed Alaouna, Demetra Demetriou, Rui Manuel Reis, Thulo Molefi, Zodwa Dlamini
Microorganisms.2022; 10(7): 1448. CrossRef
MicroRNAs: Tiny Regulators of Gene Expression with Pivotal Roles in Normal B-Cell Development and B-Cell Chronic Lymphocytic Leukemia
Katerina Katsaraki, Paraskevi Karousi, Pinelopi I. Artemaki, Andreas Scorilas, Vasiliki Pappa, Christos K. Kontos, Sotirios G. Papageorgiou
Cancers.2021; 13(4): 593. CrossRef
Metabolic Control by DNA Tumor Virus-Encoded Proteins
Martin A. Prusinkiewicz, Joe S. Mymryk
Pathogens.2021; 10(5): 560. CrossRef
Non-Coding RNAs: Strategy for Viruses’ Offensive
Alessia Gallo, Matteo Bulati, Vitale Miceli, Nicola Amodio, Pier Giulio Conaldi
Non-Coding RNA.2020; 6(3): 38. CrossRef
EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives
Keran Sun, Keqi Jia, Huifang Lv, Sai-Qi Wang, Yan Wu, Huijun Lei, Xiaobing Chen
Frontiers in Oncology.2020;[Epub] CrossRef

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Diabetes Mellitus Is Associated with Inferior Prognosis in Patients with Chronic Lymphocytic Leukemia: A Propensity Score-Matched Analysis: Rui Gao, Tian-Shuo Man, Jin-Hua Liang, Li Wang, Hua-Yuan Zhu, Wei Wu, Lei Fan, Jian-Yong Li, Tao Yang, Wei Xu; Cancer Res Treat. 2020;52(1):189-206. Published online July 1, 2019; DOI: https://doi.org/10.4143/crt.2019.122

Abstract PDF Supplementary Material PubReader ePub

Purpose
Diabetes mellitus (DM) is associated with elevated cancer risk and poor survival outcome in malignancies. The objective of this study was to evaluate the prognostic value of preexisting DM in chronic lymphocytic leukemia (CLL).
Materials and Methods
Six hundred and thirty-three subjects with newly-diagnosed CLL between 2007 and 2016 were recruited. Propensity score-matched method was performed to balance baseline characteristics and eliminate possible bias. Univariate and multivariate Cox regression analyses screened the independent risk indicators for time-to-first-treatment (TTFT) and cancer-specific survival (CSS) of CLL. Receiver operator characteristic curves and the corresponding areas under the curve assessed the predictive accuracy of CLL–International Prognostic Index (IPI) together with DM.
Results
The results showed that 111 patients had pre-existing DM. In the propensity-matched cohort, DM was correlated with inferior TTFT and CSS in CLL patients, and it was an independent prognostic factor for both CSS and TTFT. Pre-diabetics also shared undesirable prognostic outcome compared with patients with no diabetic tendency, and a positive association between longer diabetic duration and poorer prognosis of CLL was identified. DM as one additional point to CLL-IPI had larger area under the curve compared with CLL-IPI alone in CSS prediction and could improve the prognostic capacity of CLL-IPI.
Conclusion
Pre-existing DM was found to be a valuable prognostic predictor and could help predict life expectancy and build refined prognostication models for CLL.

Citations

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Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
Yuchen Zhang, Anxin Li
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Pouya Goleij, Mohammad Amin Khazeei Tabari, Ahmed Rabie Dahab Ahmed, Leena Mohamed Elamin Mohamed, Ghaida Ahmed Hamed Saleh, Malak Tarig Mohamed Abdu Hassan, Alaa Galal Mohammed Moahmmednoor, Haroon Khan
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Causal associations between site-specific cancer and diabetes risk: A two-sample Mendelian randomization study
Rong Xu, Tingjin Zheng, Chaoqun Ouyang, Xiaoming Ding, Chenjin Ge
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Association between diabetes and acute lymphocytic leukemia, acute myeloid leukemia, non-Hopkin lymphoma, and multiple myeloma
Ji Zhong Zhao, Yu Cheng Lu, Yan Min Wang, Bo Lian Xiao, Hong Yan Li, Shao Chin Lee, Li Juan Wang
International Journal of Diabetes in Developing Countries.2022; 42(4): 694. CrossRef
Increased serum level of alpha-2 macroglobulin and its production by B-lymphocytes in chronic lymphocytic leukemia
Regina Michelis, Lama Milhem, Evleen Galouk, Galia Stemer, Ariel Aviv, Tamar Tadmor, Mona Shehadeh, Lev Shvidel, Masad Barhoum, Andrei Braester
Frontiers in Immunology.2022;[Epub] CrossRef

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Albumin-to-Fibrinogen Ratio as an Independent Prognostic Parameter in Untreated Chronic Lymphocytic Leukemia: A Retrospective Study of 191 Cases: Yi-Xin Zou, Jia Qiao, Hua-Yuan Zhu, Rui-Nan Lu, Yi Xia, Lei Cao, Wei Wu, Hui Jin, Wen-Jie Liu, Jin-Hua Liang, Jia-Zhu Wu, Li Wang, Lei Fan, Wei Xu, Jian-Yong Li; Cancer Res Treat. 2019;51(2):664-671. Published online August 1, 2018; DOI: https://doi.org/10.4143/crt.2018.358

Abstract PDF PubReader ePub

Purpose
Chronic lymphocytic leukemia (CLL) is one of the most frequent type of B-cell chronic lymphoproliferative disorders and chronic inflammation takes part in the development of CLL. However, there has been no valid immune biomarker to predict the prognosis of untreated CLL patients.
Materials and Methods
In this retrospective study, we analyzed the clinical correlations and prognostic value of albumin-to-fibrinogen ratio (AFR) detected at diagnosis in 191 CLL patients.
Results
The cut-off value of AFR was 9.7 calculated by X-tile. Patients who were more than 65 years old were often accompanied by low level of AFR (p < 0.001). Survival analysis showed that patients with low level of AFR had shorter overall survival (OS) than patients with high level of AFR (p < 0.001). Multivariate analysis illustrated that AFR had a negative impact on OS (p=0.003) and was independent of parameters involved in CLL international prognostic index and other prognostic markers such as CD38 and ZAP-70.
Conclusion
These data provide a comprehensive view of AFR and shows that AFR at diagnosis is an adverse prognostic factor in untreated CLL patients.

Citations

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Case Report

Progressive Multifocal Leukoencephalopathy after Ibrutinib Therapy for Chronic Lymphocytic Leukemia: Mathias Lutz, Arik B. Schulze, Elisabeth Rebber, Stefanie Wiebe, Tarek Zoubi, Oliver M. Grauer, Torsten Keßler, Andrea Kerkhoff, Georg Lenz, Wolfgang E. Berdel; Cancer Res Treat. 2017;49(2):548-552. Published online July 12, 2016; DOI: https://doi.org/10.4143/crt.2016.110

Abstract PDF PubReader ePub

Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton’s tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association.

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Original Article

A Clinical Study on Patients with Chronic Lymphocytic Leukemia: Jeon Ho Yang, Hyeon Soo Shin, Young Sik Jung, Jun Ho Whang, Dong Gun Shin, Sang Kyun Sohn, Kyu Bo Lee, Kee Suk Whang; J Korean Cancer Assoc. 1997;29(6):1106-1113.

Abstract PDF: PURPOSE
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in western countries but it has been reported rarely in Korea. The purpose of this study was to evaluate the clinical characteristics, treatment responses and prognosis of the patients with CLL.
MATERIALS AND METHODS
We retrospectively reviewed the medical records of 17 patients with CLL diagnosed at the Catholic University of Taegu-Hyosung & Kyungpook National University Hospital from Jan. 1986 to Mar. 1996.
RESULTS
There were 9 males and 8 females and the mean age was 55 years. The majority of patients had systemic symptoms (77%) and advanced clinical stage (Binet stage C, 70%) at the time of diagnosis. The bone marrow histology was reviewed in 13 cases and patients were subdivided into those with a diffuse (9cases) and nondiffuse (4cases) pattern of bone marrow histology. In patients with advanced clinical stage, diffuse pattern was predominated and showed poor survival. 14 patients were treated with chlorambucil/steroid or combination chemotherapy. Among the 13 evaluable patients, 1 (8%) achieved a complete response and 7 (54%) achieved partial responses, and median survival duration was 18months. 11 patients died after 2~18 months of follow-up and infection was the main cause of death.
CONCLUSION
Poor prognostic factors, such as high blood lymphocyte counts, diffuse bone marrow involvement pattern & advanced clinical stage, are common in our patients at presentation & showed poor survival.

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