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Wang CC, Lu DD, Shen MH, Chen RL, Zhang ZH, Lv JH. Clinical value of Cyclin D1 and P21 in the differential diagnosis of papillary thyroid carcinoma. Diagn Pathol 2023; 18:123. [PMID: 37951919 PMCID: PMC10638720 DOI: 10.1186/s13000-023-01410-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 10/29/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND With the continuous discovery of new borderline thyroid lesions and benign and malignant "gray areas", coupled with the limitations of traditional immune indicators, the differential diagnosis of papillary thyroid carcinoma (PTC) has become more difficult. Cyclin D1 and P21 are cell cycle regulators involved in the occurrence and metastasis of multiple tumors, including PTC, but their specific functions are unclear. METHODS In our study, immunohistochemical staining was used to explore the expression of Cyclin D1 and P21 in PTC, paracancerous tissue, follicular adenoma (FA) and papillary thyroid hyperplasia. In addition, their relationship with the clinicopathological features of PTC and their differential diagnostic value in distinguishing between intralymph node PTC metastases and intralymph node ectopic thyroid tissue were studied. RESULTS Among 200 primary PTC lesions, Cyclin D1 and P21 were found to be expressed in 186 (93.00%) and 177 (88.50%), respectively, and their expression levels were significantly higher in PTC tissue than in adjacent tissue, FA tissue and papillary thyroid hyperplasia tissue (P < 0.05). The expression levels of Cyclin D1 and P21 were positively correlated with tumor size and lymph node metastasis (P < 0.05) but not with sex, age, number of tumor lesions, histological subtype, chronic lymphocytic thyroiditis or TNM stage (P < 0.05). The expression levels of Cyclin D1 and P21 were significantly correlated (P < 0.05). The positivity rates of Cyclin D1 and P21 in intralymph node PTC metastases were 97.96% (48/49) and 89.80% (44/49), respectively, which were significantly higher than those in intralymph node ectopic thyroid tissue (P < 0.05). The sensitivity (Se) and negative predictive value (NPV) of Cyclin D1 and P21 detection alone or in combination were higher than those of the combined detection of the classical antibody markers CK19, HBME-1 and Galectin-3. Besides, the Se, Sp, PPV and NPV of Cyclin D1 and P21 in differentiating intralymph node PTC metastases and intralymph node ectopic thyroid tissue were higher. CONCLUSIONS The results of our study show that Cyclin D1 and P21 are highly sensitive and specific markers for the diagnosis of PTC that are superior to traditional classical antibodies. And, these two markers are of great value in the differential diagnosis of intralymph node PTC metastases and intralymph node ectopic thyroid tissue.
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Affiliation(s)
- Chen-Chen Wang
- Department of Pathology, Gusu School, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China
| | - Dan-Dan Lu
- Department of Pathology, Gusu School, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China
| | - Ming-Hong Shen
- Department of Pathology, Gusu School, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China
| | - Ru-Lei Chen
- Department of Pathology, Gusu School, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China
| | - Zhi-Hong Zhang
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Jing-Huan Lv
- Department of Pathology, Gusu School, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China.
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Zheng YC, Zhao JW, Guo X, Yi SH, Tao Y, Li CW. [IGL-CCND1 positive mantle cell lymphoma: a case report and literature review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:598-601. [PMID: 37749044 PMCID: PMC10509628 DOI: 10.3760/cma.j.issn.0253-2727.2023.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Indexed: 09/27/2023]
Affiliation(s)
- Y C Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - J W Zhao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - X Guo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - S H Yi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Y Tao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - C W Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
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Zabihi M, Lotfi R, Yousefi AM, Bashash D. Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities. J Cancer Res Clin Oncol 2023; 149:1585-1606. [PMID: 35781526 DOI: 10.1007/s00432-022-04135-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/13/2022] [Indexed: 12/20/2022]
Abstract
The discussion on cell proliferation cannot be continued without taking a look at the cell cycle regulatory machinery. Cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) are valuable members of this system and their equilibrium guarantees the proper progression of the cell cycle. As expected, any dysregulation in the expression or function of these components can provide a platform for excessive cell proliferation leading to tumorigenesis. The high frequency of CDK abnormalities in human cancers, together with their druggable structure has raised the possibility that perhaps designing a series of inhibitors targeting CDKs might be advantageous for restricting the survival of tumor cells; however, their application has faced a serious concern, since these groups of serine-threonine kinases possess non-canonical functions as well. In the present review, we aimed to take a look at the biology of CDKs and then magnify their contribution to tumorigenesis. Then, by arguing the bright and dark aspects of CDK inhibition in the treatment of human cancers, we intend to reach a consensus on the application of these inhibitors in clinical settings.
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Affiliation(s)
- Mitra Zabihi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Lotfi
- Clinical Research Development Center, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Nassereldine H, Mohty R, Awada H, Abou Dalle I, El-Cheikh J, Bazarbachi A. Mantle cell lymphoma negative for t(11,14) involving the kidneys: a case report. J Med Case Rep 2022; 16:254. [PMID: 35768844 PMCID: PMC9245262 DOI: 10.1186/s13256-022-03470-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 05/24/2022] [Indexed: 11/28/2022] Open
Abstract
Background Mantle cell lymphoma is the rarest subtype of non-Hodgkin’s lymphoma. It can exhibit diverse extranodal manifestations. However, renal involvement is uncommon, and if it occurs, it usually only gets detected postmortem. There are several mechanisms by which mantle cell lymphoma can damage the kidneys. Renal failure is a potential complication, and prompt evaluation and diagnosis are critical steps to prevent long-term complications. Case presentation We present the case of a 75-year-old non-Hispanic White male with past medical history significant for hypertension and dyslipidemia, presenting with fever, weight loss, and night sweats. Work-up showed markedly elevated white blood cells, multiple enlarged lymph nodes, and a kidney mass. The patient was diagnosed with mantle cell lymphoma with kidney involvement confirmed with a kidney biopsy. His disease was positive for cyclin D1 overexpression despite t(11; 14) absence. The patient received six cycles of alternating vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone then dexamethasone, high-dose cytarabine, and oxaliplatin, after which he was maintained on ibrutinib and rituximab, with resolution of symptoms and disease regression. Conclusion We present a case of a rare presentation of Mantle cell lymphoma while describing the clinical presentation and diagnostic and treatment approaches. This case report can assist physicians in the clinical work-up and treatment of patients with similar diagnosis or presentation.
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Affiliation(s)
| | - Razan Mohty
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 113-6044, Beirut, Lebanon
| | - Hussein Awada
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Iman Abou Dalle
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 113-6044, Beirut, Lebanon
| | - Jean El-Cheikh
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 113-6044, Beirut, Lebanon
| | - Ali Bazarbachi
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 113-6044, Beirut, Lebanon.
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The E3 Ubiquitin Ligase Fbxo4 Functions as a Tumor Suppressor: Its Biological Importance and Therapeutic Perspectives. Cancers (Basel) 2022; 14:cancers14092133. [PMID: 35565262 PMCID: PMC9101129 DOI: 10.3390/cancers14092133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/22/2022] [Accepted: 04/23/2022] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Fbxo4 is an E3 ubiquitin ligase that requires the formation of a complex with S-phase kinase-associated protein 1 and Cullin1 to catalyze the ubiquitylation of its substrates. Moreover, Fbxo4 depends on the existence of posttranslational modifications and/or co-factor to be activated to perform its biological functions. The well-known Fbxo4 substrates have oncogenic or oncogene-like activities, for example, cyclin D1, Trf1/Pin2, p53, Fxr1, Mcl-1, ICAM-1, and PPARγ; therefore, Fbxo4 is defined as a tumor suppressor. Biologically, Fbxo4 regulates cell cycle progression, DNA damage response, tumor metabolism, cellular senescence, metastasis and tumor cells’ response to chemotherapeutic compounds. Clinicopathologically, the expression of Fbxo4 is associated with patients’ prognosis depending on different tumor types. Regarding to its complicated regulation, more in-depth studies are encouraged to dissect the detailed molecular mechanisms to facilitate developing new treatment through targeting Fbxo4. Abstract Fbxo4, also known as Fbx4, belongs to the F-box protein family with a conserved F-box domain. Fbxo4 can form a complex with S-phase kinase-associated protein 1 and Cullin1 to perform its biological functions. Several proteins are identified as Fbxo4 substrates, including cyclin D1, Trf1/Pin2, p53, Fxr1, Mcl-1, ICAM-1, and PPARγ. Those factors can regulate cell cycle progression, cell proliferation, survival/apoptosis, and migration/invasion, highlighting their oncogenic or oncogene-like activities. Therefore, Fbxo4 is defined as a tumor suppressor. The biological functions of Fbxo4 make it a potential candidate for developing new targeted therapies. This review summarizes the gene and protein structure of Fbxo4, the mechanisms of how its expression and activity are regulated, and its substrates, biological functions, and clinicopathological importance in human cancers.
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Chauhan S, Sen S, Pushker N, Tandon R, Kashyap S, Vanathi M, Bajaj MS. Clinical Significance of Cyclin Expression Profiling in Ocular Surface Squamous Neoplasia. Appl Immunohistochem Mol Morphol 2022; 30:197-203. [PMID: 34657082 DOI: 10.1097/pai.0000000000000981] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 09/06/2021] [Indexed: 11/25/2022]
Abstract
Ocular surface squamous neoplasia (OSSN) can recur, metastasize, and even cause death. Cyclins regulate the cell cycle progression at different phases and its dysregulation is associated with uncontrollable cell growth and malignant transformation of the cell. Overexpression of cyclin has been reported in various malignancies and is associated with poor prognosis. However, the role of cyclins in OSSN remains unexplored. This study has been designed to assess the prognostic significance of cyclin (cyclin B1, E1, and D1) immunoexpression in 100 OSSN patients. The targeted proteins demonstrated overexpression of cyclin B1, cyclin E1, and cyclin D1 in 55%, 37%, and 56% OSSN cases prospectively. A gradual and significant increase in the cyclin B1 (P=0.01) and cyclin D1 (P=0.005) expression was seen from Tis to the T4 category. Overexpression of cyclin B1 was associated with poor disease-free survival and worst prognosis in both early (P=0.03) as well as advanced T staged (P=0.038) OSSN patients. Overexpression of cyclin E1 was associated with worst disease-free survival (P=0.01) and poor prognosis in advanced stage OSSN patients. Our findings suggest that cyclin B1 and cyclin E1 have prognostic relevance in OSSN patients, and therefore are recommended for detecting high-risk category cases. A significant increase in the expression of cyclins from early to advanced stage indicates that cyclins play an important role in the pathogenesis of OSSN patients.
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Affiliation(s)
| | | | | | - Radhika Tandon
- Cornea and External Disease, Cataract and Refractive, Ocular Oncology and Low Vision Services
| | | | - Murugesan Vanathi
- Cornea and Ocular Surface, Cataract and Refractive Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
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Mandigo AC, Tomlins SA, Kelly WK, Knudsen KE. Relevance of pRB Loss in Human Malignancies. Clin Cancer Res 2022; 28:255-264. [PMID: 34407969 PMCID: PMC9306333 DOI: 10.1158/1078-0432.ccr-21-1565] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/24/2021] [Accepted: 08/10/2021] [Indexed: 01/07/2023]
Abstract
The retinoblastoma tumor suppressor protein (pRB) is a known regulator of cell-cycle control; however, recent studies identified critical functions for pRB in regulating cancer-associated gene networks that influence the DNA damage response, apoptosis, and cell metabolism. Understanding the impact of these pRB functions on cancer development and progression in the clinical setting will be essential, given the prevalence of pRB loss of function across disease types. Moreover, the current state of evidence supports the concept that pRB loss results in pleiotropic effects distinct from tumor proliferation. Here, the implications of pRB loss (and resultant pathway deregulation) on disease progression and therapeutic response will be reviewed, based on clinical observation. Developing a better understanding of the pRB-regulated pathways that underpin the aggressive features of pRB-deficient tumors will be essential for further developing pRB as a biomarker of disease progression and for stratifying pRB-deficient tumors into more effective treatment regimens.
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Affiliation(s)
- Amy C. Mandigo
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Scott A. Tomlins
- Departments of Pathology and Urology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - William K. Kelly
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Karen E. Knudsen
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Corresponding Author: Karen E. Knudsen, Thomas Jefferson University, 233 South 10th Street, BLSB 1050, Philadelphia, PA 19107. Phone: 215-503-5692; E-mail:
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Bortezomib in combination with fludarabine plus cyclophosphamide for patients with relapsed or refractory mantle-cell lymphoma: results of the LYM-4003 study. Ann Hematol 2021; 100:2961-2968. [PMID: 34331111 DOI: 10.1007/s00277-021-04619-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 07/18/2021] [Indexed: 10/20/2022]
Abstract
This study aimed to identify the maximum-tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine (B-FC) in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL (rrMCL). Forty patients were enrolled between April 8, 2011, and October 10, 2015. The MTD of cyclophosphamide was identified to be 250 mg/m2 days 1-2. At a median follow-up of 31.6 months (13.5-47.4), among 32 patients in phase 2, 10 (31%) had a complete response and 13 (41%) had a partial response. The median progression-free survival was 21 months (95% CI 7.3-34.7), and the median overall survival was 32.4 months (95% CI 17.8-47.0). Grade 3-4 hematologic AEs included neutropenia (27%) and thrombocytopenia (39%). The B-FC regimen has satisfactory responses and manageable toxicities in rrMCL patients (ClinicalTrials.gov NCT01322776).
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Abstract
The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.
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10
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Torre-Castro J, Moya-Martínez C, Núñez-Hipólito L, Mendoza-Cembranos MD, Eraña-Tomás I, Jo-Velasco M, Saus C, Solares J, Requena L, Santonja C. Three additional cases of non-neural granular cell tumor with novel immunohistochemical findings. J Cutan Pathol 2020; 47:1026-1032. [PMID: 32643817 DOI: 10.1111/cup.13801] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/18/2020] [Accepted: 07/01/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Non-neural granular cell tumor (NNGCT) is an uncommon neoplasm of controversial histogenesis and its histopathologic differential diagnosis includes, in addition to conventional GCT, other dermal tumors that may exhibit granular cell change. METHODS Three patients with a diagnosis of NNGCT were identified in the authors' files. Hematoxylin and eosin-stained sections and immunohistochemical studies were performed. RESULTS Histopathological study of the three lesions showed dermal proliferation of granular cells arranged in thick fascicles between collagen bundles. The lesions showed positivity for Factor XIIIa, CD163, CD68, NKIC3, vimentin, ALK, fascin, and cyclin D1. CONCLUSION To our knowledge, positivity for cyclin D1 has not been reported to date in NNGCT. In borderline cases, where the diagnosis is unclear despite histopathologic and immunohistochemical findings, positivity for cyclin D1 may favor the diagnosis of NNGCT. Further investigations to assess the differentiation of this rare neoplasm are needed.
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Affiliation(s)
- Juan Torre-Castro
- Department of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Cristina Moya-Martínez
- Department of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Lucía Núñez-Hipólito
- Department of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | | | - Itziar Eraña-Tomás
- Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Margarita Jo-Velasco
- Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Carles Saus
- Department of Pathology, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Julia Solares
- Department of Pathology, Hospital San Pedro de Alcántara, Cáceres, Spain
| | - Luis Requena
- Department of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Carlos Santonja
- Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
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Liu Y, Liu Q, Wang Z, Chen M, Chen Y, Li X, Huang D, Fan S, Xiong W, Li G, Zhang W. Upregulation of cyclin D1 can act as an independent prognostic marker for longer survival time in human nasopharyngeal carcinoma. J Clin Lab Anal 2020; 34:e23298. [PMID: 32697404 PMCID: PMC7439355 DOI: 10.1002/jcla.23298] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 01/14/2023] Open
Abstract
Background Cyclin D1 is an essential part of oncogenic transformation. We previously proved that cyclin D1 was upregulated in nasopharyngeal carcinoma (NPC) and promoted the NPC cell proliferation. But the association between cyclin D1 and the clinical outcome of NPC has not yet been determined. The study explores the possible relevance between the cyclin D1 expression and clinical parameters and its predictive value of prognosis in NPC patients. Methods We analyzed the clinical data from 379 NPC patients and 112 non‐NPC patients in our previous study, which made further statistics. Receiver operating curve (ROC) was applied to select the optimal cutoff points. By analyzing the clinical data from 101 NPC patients using Chi‐squared test, we estimated the relationship between the cyclin D1 expression level and clinicopathological parameters. We also used Kaplan‐Meier method and log‐rank test assess and compared the disease‐free survival (DFS) rate and overall survival (OS) rate. The Cox proportional hazards model was adopted to perform the univariate and multivariate analyses. Result Receiver operating curve analysis reported that cyclin D1 was used to differentiate between NPC patients and non‐NPC patients (P < .001, sensitivity: 53.6%, specificity: 85.7%, AUC = 0.752). Cyclin D1 was positively correlated with lymph node metastasis (P = .015). A survival analysis of the 101 NPC patients indicated that the positive expression of cyclin D1 was predictive of a good prognosis (DFS: P = .010, OS: P = .019). Multivariate analysis showed that cyclin D1 could be used independently to predict NPC patients' prognosis (DFS: P = .038). Conclusion The overexpression of cyclin D1 is a good prognostic marker for NPC.
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Affiliation(s)
- Yijun Liu
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qingluan Liu
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhicheng Wang
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Meilin Chen
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yi Chen
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiayu Li
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Donghai Huang
- Xiangya Hospital, Central South University, Changsha, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Xiong
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Guiyuan Li
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Wenling Zhang
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, China
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Cyclin D degradation by E3 ligases in cancer progression and treatment. Semin Cancer Biol 2020; 67:159-170. [PMID: 32006569 DOI: 10.1016/j.semcancer.2020.01.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/20/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022]
Abstract
D cyclins include three isoforms: D1, D2, and D3. D cyclins heterodimerize with cyclin-dependent kinase 4/6 (CDK4/6) to form kinase complexes that can phosphorylate and inactivate Rb. Inactivation of Rb triggers the activation of E2F transcription factors, which in turn regulate the expression of genes whose products drive cell cycle progression. Because D-type cyclins function as mitogenic sensors that link growth factor signaling directly with G1 phase progression, it is not surprising that D cyclin accumulation is dysregulated in a variety of human tumors. Elevated expression of D cyclins results from gene amplification, increased gene transcription and protein translation, decreased microRNA levels, and inefficiency or loss of ubiquitylation-mediated protein degradation. This review focuses on the clinicopathological importance of D cyclins, how dysregulation of Ubiquitin-Proteasome System (UPS) contributes to the overexpression of D cyclins, and the therapeutic potential through targeting D cyclin-related machinery in human tumors.
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Abstract
B cell development and activation are accompanied by dynamic genetic alterations including V(D)J rearrangements and immunoglobulin-gene somatic hypermutation and class-switch recombination. Abnormalities in these genetic events can cause chromosomal translocations and genomic mutations, leading to altered expression and function of genes involved in B cell survival or proliferation and consequently B lymphomagenesis. In fact, B cell lymphoma accounts for 95% of the lymphomas. In this chapter, we summarize the morphology, immunophenotypes, clinical features, genetic defects that cause the malignancies, treatments, and prognosis of the most prevalent types of B cell lymphomas, including typical precursor B cell malignance (B-ALL/LBL) and mature B cell lymphoma (Hodgkin lymphoma and B cell non-Hodgkin lymphoma).
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Affiliation(s)
- Xin Meng
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Qing Min
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ji-Yang Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Tong Y, Song Y, Deng S. Combined analysis and validation for DNA methylation and gene expression profiles associated with prostate cancer. Cancer Cell Int 2019; 19:50. [PMID: 30867653 PMCID: PMC6399908 DOI: 10.1186/s12935-019-0753-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 02/08/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a malignancy cause of cancer deaths and frequently diagnosed in male. This study aimed to identify tumor suppressor genes, hub genes and their pathways by combined bioinformatics analysis. METHODS A combined analysis method was used for two types of microarray datasets (DNA methylation and gene expression profiles) from the Gene Expression Omnibus (GEO). Differentially methylated genes (DMGs) were identified by the R package minfi and differentially expressed genes (DEGs) were screened out via the R package limma. A total of 4451 DMGs and 1509 DEGs, identified with nine overlaps between DMGs, DEGs and tumor suppressor genes, were screened for candidate tumor suppressor genes. All these nine candidate tumor suppressor genes were validated by TCGA (The Cancer Genome Atlas) database and Oncomine database. And then, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed by DAVID (Database for Annotation, Visualization and Integrated Discovery) database. Protein-protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. At last, Kaplan-Meier analysis was performed to validate these genes. RESULTS The candidate tumor suppressor genes were IKZF1, PPM1A, FBP1, SMCHD1, ALPL, CASP5, PYHIN1, DAPK1 and CASP8. By validation in TCGA database, PPM1A, DAPK1, FBP1, PYHIN1, ALPL and SMCHD1 were significant. The hub genes were FGFR1, FGF13 and CCND1. These hub genes were identified from the PPI network, and sub-networks revealed by these genes were involved in significant pathways. CONCLUSION In summary, the study indicated that the combined analysis for identifying target genes with PCa by bioinformatics tools promote our understanding of the molecular mechanisms and underlying the development of PCa. And the hub genes might serve as molecular targets and diagnostic biomarkers for precise diagnosis and treatment of PCa.
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Affiliation(s)
- Yanqiu Tong
- Laboratory of Forensic Medicine and Biomedical Informatics, Chongqing Medical University, Chongqing, 400016 People’s Republic of China
- School of Humanity, Chongqing Jiaotong University, Chongqing, 400074 People’s Republic of China
| | - Yang Song
- Department of Device, Chongqing Medical University, Chongqing, 400016 People’s Republic of China
| | - Shixiong Deng
- Laboratory of Forensic Medicine and Biomedical Informatics, Chongqing Medical University, Chongqing, 400016 People’s Republic of China
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15
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Sandoval-Sus JD, Faramand R, Chavez J, Puri S, Parra P, Sokol L, Kharfan-Dabaja MA, Shah B, Ayala E. Allogeneic hematopoietic cell transplantation is potentially curative in mantle cell lymphoma: results from a single institution study. Leuk Lymphoma 2018; 60:309-316. [DOI: 10.1080/10428194.2018.1468894] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Jose D. Sandoval-Sus
- Malignant Hematology, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
| | - Rawan Faramand
- Malignant Hematology, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
| | - Julio Chavez
- Malignant Hematology, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
| | - Sonam Puri
- Malignant Hematology, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
| | - Paola Parra
- Internal Medicine, Universidad Autonoma de Bucaramanga Facultad de Ciencias de la Salud, Bucaramanga, Colombia
| | - Lubomir Sokol
- Malignant Hematology, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
| | | | - Bijal Shah
- Malignant Hematology, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
| | - Ernesto Ayala
- Blood and Marrow Transplantation, University of South Florida/Moffitt Cancer Center, Tampa, FL, USA
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16
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Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer 2018; 17:57. [PMID: 29455639 PMCID: PMC5817726 DOI: 10.1186/s12943-018-0779-z] [Citation(s) in RCA: 473] [Impact Index Per Article: 67.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022] Open
Abstract
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.
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Affiliation(s)
- Simar Pal Singh
- Department of Pulmonary Medicine, Room Ee2251a, Erasmus MC Rotterdam, PO Box 2040, NL 3000, CA, Rotterdam, The Netherlands.,Department of Immunology, Rotterdam, The Netherlands.,Post graduate school Molecular Medicine, Rotterdam, The Netherlands
| | - Floris Dammeijer
- Department of Pulmonary Medicine, Room Ee2251a, Erasmus MC Rotterdam, PO Box 2040, NL 3000, CA, Rotterdam, The Netherlands.,Post graduate school Molecular Medicine, Rotterdam, The Netherlands.,Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Room Ee2251a, Erasmus MC Rotterdam, PO Box 2040, NL 3000, CA, Rotterdam, The Netherlands.
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17
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Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol 2017; 92:806-813. [PMID: 28699667 DOI: 10.1002/ajh.24797] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 05/18/2017] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years. DIAGNOSIS Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION The MCL International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median OS for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group. RISK-ADAPTED THERAPY For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytotoxic Regimen followed by autologous stem cell transplantation should be considered. Rituximab maintenance after autologous stem cell transplantation has also improved the progression-free and overall survival. For older symptomatic MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. In addition, rituximab maintenance therapy may prolong the progression-free survival. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), lenalidamide (anti-angiogenesis) and Ibruitinib (Bruton's Tyrosine Kinase [BTK] inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients. Clinical trials with novel agents are always a consideration for MCL patients.
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Affiliation(s)
- Julie M Vose
- Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, Nebraska, 68198-7680
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18
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Mantle Cell Lymphoma: Contemporary Diagnostic and Treatment Perspectives in the Age of Personalized Medicine. Hematol Oncol Stem Cell Ther 2017; 10:99-115. [PMID: 28404221 DOI: 10.1016/j.hemonc.2017.02.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 02/01/2017] [Accepted: 02/20/2017] [Indexed: 11/22/2022] Open
Abstract
Mantle cell lymphoma is a clinically heterogeneous disease occurring within a heterogeneous patient population, highlighting a need for personalized therapy to ensure optimal outcomes. It is therefore critical to understand the benefits and risks associated with both intensive and deintensified approaches. In the following review we provide a therapeutic roadmap to strategically guide treatment for newly diagnosed and relapsed/refractory patients highlighting pivotal and recently published results involving known and novel therapies.
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19
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Ramos-García P, Gil-Montoya JA, Scully C, Ayén A, González-Ruiz L, Navarro-Triviño FJ, González-Moles MA. An update on the implications of cyclin D1 in oral carcinogenesis. Oral Dis 2017; 23:897-912. [DOI: 10.1111/odi.12620] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 11/07/2016] [Accepted: 12/01/2016] [Indexed: 12/11/2022]
Affiliation(s)
- P Ramos-García
- School of Dentistry; University of Granada; Granada Spain
| | - JA Gil-Montoya
- School of Dentistry; University of Granada; Granada Spain
- Instituto de Biomedicina; University of Granada; Granada Spain
| | - C Scully
- University College of London; London UK
| | - A Ayén
- School of Medicine; University of Granada; Granada Spain
| | - L González-Ruiz
- Servicio de Dermatología; Hospital General Universitario de Ciudad Real; Ciudad Real Spain
| | - FJ Navarro-Triviño
- Servicio de Dermatología; Complejo Hospitalario San Cecilio; Granada Spain
| | - MA González-Moles
- School of Dentistry; University of Granada; Granada Spain
- Instituto de Biomedicina; University of Granada; Granada Spain
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20
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Abstract
The recent application of next-generation sequencing technologies lead to significant improvements in our understanding of genetic underpinnings of non-Hodgkin lymphomas with identification of an unexpectedly high number of novel mutation targets across the different B-cell lymphoma entities. These recently discovered molecular lesions are expected to have a major impact on development of novel biomarkers and targeted therapies as well as patient stratification based on the underlying genetic profile. This review will cover the major discoveries in B-cell lymphomas using next-generation sequencing technologies over the last few years, highlighting alterations associated with relapse and progression of these diseases.
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Affiliation(s)
- Csaba Bödör
- MTA-SE Lendulet Molecular Oncohematology Research Group, Budapest, Hungary.,1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Lilla Reiniger
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. .,2nd Department of Pathology, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
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21
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Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl) 2016; 94:1313-1326. [PMID: 27695879 PMCID: PMC5145738 DOI: 10.1007/s00109-016-1475-3] [Citation(s) in RCA: 480] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 09/06/2016] [Accepted: 09/13/2016] [Indexed: 12/15/2022]
Abstract
Mammalian cells encode three D cyclins (D1, D2, and D3) that coordinately function as allosteric regulators of cyclin-dependent kinase 4 (CDK4) and CDK6 to regulate cell cycle transition from G1 to S phase. Cyclin expression, accumulation, and degradation, as well as assembly and activation of CDK4/CDK6 are governed by growth factor stimulation. Cyclin D1 is more frequently dysregulated than cyclin D2 or D3 in human cancers, and as such, it has been more extensively characterized. Overexpression of cyclin D1 results in dysregulated CDK activity, rapid cell growth under conditions of restricted mitogenic signaling, bypass of key cellular checkpoints, and ultimately, neoplastic growth. This review discusses cyclin D1 transcriptional, translational, and post-translational regulations and its biological function with a particular focus on the mechanisms that result in its dysregulation in human cancers.
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Affiliation(s)
- Shuo Qie
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St, Charleston, SC, 29425, USA
| | - J Alan Diehl
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St, Charleston, SC, 29425, USA.
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22
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Song JY, Song L, Herrera AF, Venkatarman G, Murata-Collins JL, Bedell V, Chen YY, Kim YS, Tadros R, Nathwani BN, Weisenburger DD, Feldman AL. Cyclin D1 expression in peripheral T-cell lymphomas. Mod Pathol 2016; 29:1306-1312. [PMID: 27469326 PMCID: PMC5576450 DOI: 10.1038/modpathol.2016.136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/02/2016] [Accepted: 06/02/2016] [Indexed: 01/25/2023]
Abstract
Cyclin D1 is an important regulator of the cell cycle and overexpression of this protein by immunohistochemistry is characteristically seen in mantle cell lymphoma and other B-cell neoplasms. However, little is known about the expression of this protein in T-cell lymphomas. Cyclin-dependent kinase pathway inhibitors are in development, therefore identifying cyclin D1-positive T-cell lymphomas may provide a therapeutic target in a disease where novel treatments are urgently needed. We collected 200 peripheral T-cell lymphomas from three institutions including the following types of cases: 34 anaplastic large cell lymphoma, ALK+, 44 anaplastic large cell lymphoma, ALK negative, 68 peripheral T-cell lymphomas, not otherwise specified, 24 angioimmunoblastic T-cell lymphomas, 7 extranodal NK/T-cell lymphomas, 4 enteropathy associated T-cell lymphomas, 3 hepatosplenic T-cell lymphomas, 12 cutaneous T-cell lymphomas, and 4 large granular lymphocytic leukemias. Immunohistochemical stains for cyclin D1 protein (SP4 clone) were performed on paraffin-embedded tissue. In a subset of cases, IGH/CCND1 fluorescence in situ hybridization analysis was also performed. Cyclin D1 staining was predominantly seen in anaplastic large cell lymphoma, including 8 of 34 cases with ALK+ anaplastic large cell lymphoma (24%), and 3 of 44 cases of ALK-negative (7%) anaplastic large cell lymphoma. Three cases of peripheral T-cell lymphoma, not otherwise specified, were also positive (3/68, 4%). All other T-cell lymphomas were negative for cyclin D1. In four of the cyclin D1-positive T-cell lymphomas by immunohistochemistry, fluorescence in situ hybridization analysis was negative for IGH/CCND1 translocation or extra copies of the CCND1 gene. Cyclin D1 overexpression by immunohistochemistry is not limited to B-cell lymphomas and is also observed in some peripheral T-cell lymphomas, particularly in anaplastic large cell lymphoma, ALK+. Cyclin D1 expression was not associated with extra copies or translocation of the CCND1 gene. Cyclin D1 overexpression may be the result of a post-translational phenomenon and may represent a potential therapeutic target using agents that target the cyclin-dependent kinase pathway.
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Affiliation(s)
- Joo Y. Song
- Department of Pathology, City of Hope National Medical Center, Duarte, CA,Corresponding author: Joo Y. Song, MD, City of Hope National Medical Center, Department of Pathology, 1500 E. Duarte Rd., Duarte, CA 91010,
| | - Liping Song
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Alex F. Herrera
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
| | | | | | - Victoria Bedell
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Yuan Yuan Chen
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Young S. Kim
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Reda Tadros
- Department of Pathology, Chino Valley Medical Center, Chino, CA
| | - Bharat N. Nathwani
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | | | - Andrew L. Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
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23
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Lam G, Xian RR, Li Y, Burns KH, Beemon KL. Lack of TERT Promoter Mutations in Human B-Cell Non-Hodgkin Lymphoma. Genes (Basel) 2016; 7:genes7110093. [PMID: 27792139 PMCID: PMC5126779 DOI: 10.3390/genes7110093] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 09/21/2016] [Accepted: 10/13/2016] [Indexed: 11/23/2022] Open
Abstract
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of immune cell neoplasms that comprise molecularly distinct lymphoma subtypes. Recent work has identified high frequency promoter point mutations in the telomerase reverse transcriptase (TERT) gene of different cancer types, including melanoma, glioma, liver and bladder cancer. TERT promoter mutations appear to correlate with increased TERT expression and telomerase activity in these cancers. In contrast, breast, pancreatic, and prostate cancer rarely demonstrate mutations in this region of the gene. TERT promoter mutation prevalence in NHL has not been thoroughly tested thus far. We screened 105 B-cell lymphoid malignancies encompassing nine NHL subtypes and acute lymphoblastic leukemia, for TERT promoter mutations. Our results suggest that TERT promoter mutations are rare or absent in most NHL. Thus, the classical TERT promoter mutations may not play a major oncogenic role in TERT expression and telomerase activation in NHL.
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Affiliation(s)
- Gary Lam
- Department of Biology, Johns Hopkins University, Baltimore, MD 21210, USA.
| | - Rena R Xian
- Department of Pathology, Johns Hopkins Medical Institutes, Baltimore, MD 212105, USA.
- Department of Pathology, University of California Los Angeles, Los Angeles, CA 90095, USA.
| | - Yingying Li
- Department of Biology, Johns Hopkins University, Baltimore, MD 21210, USA.
| | - Kathleen H Burns
- Department of Pathology, Johns Hopkins Medical Institutes, Baltimore, MD 212105, USA.
| | - Karen L Beemon
- Department of Biology, Johns Hopkins University, Baltimore, MD 21210, USA.
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24
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Badia R, Pujantell M, Riveira-Muñoz E, Puig T, Torres-Torronteras J, Martí R, Clotet B, Ampudia RM, Vives-Pi M, Esté JA, Ballana E. The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells. PLoS Pathog 2016; 12:e1005829. [PMID: 27541004 PMCID: PMC4991798 DOI: 10.1371/journal.ppat.1005829] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 07/27/2016] [Indexed: 01/09/2023] Open
Abstract
Macrophages are a heterogeneous cell population strongly influenced by differentiation stimuli that become susceptible to HIV-1 infection after inactivation of the restriction factor SAMHD1 by cyclin-dependent kinases (CDK). Here, we have used primary human monocyte-derived macrophages differentiated through different stimuli to evaluate macrophage heterogeneity on cell activation and proliferation and susceptibility to HIV-1 infection. Stimulation of monocytes with GM-CSF induces a non-proliferating macrophage population highly restrictive to HIV-1 infection, characterized by the upregulation of the G1/S-specific cyclin D2, known to control early steps of cell cycle progression. Knockdown of cyclin D2, enhances HIV-1 replication in GM-CSF macrophages through inactivation of SAMHD1 restriction factor by phosphorylation. Co-immunoprecipitation experiments show that cyclin D2 forms a complex with CDK4 and p21, a factor known to restrict HIV-1 replication by affecting the function of the downstream cascade that leads to SAMHD1 deactivation. Thus, we demonstrate that cyclin D2 acts as regulator of cell cycle proteins affecting SAMHD1-mediated HIV-1 restriction in non-proliferating macrophages.
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Affiliation(s)
- Roger Badia
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Maria Pujantell
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Eva Riveira-Muñoz
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Teresa Puig
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Javier Torres-Torronteras
- Research Group on Neuromuscular and Mitochondrial Disorders, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Ramón Martí
- Research Group on Neuromuscular and Mitochondrial Disorders, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Bonaventura Clotet
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Rosa M. Ampudia
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Biomedical Network Research Centre on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
| | - Marta Vives-Pi
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Biomedical Network Research Centre on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
| | - José A. Esté
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- * E-mail: (JAE); (EB)
| | - Ester Ballana
- AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- * E-mail: (JAE); (EB)
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25
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Augello MA, Berman-Booty LD, Carr R, Yoshida A, Dean JL, Schiewer MJ, Feng FY, Tomlins SA, Gao E, Koch WJ, Benovic JL, Diehl JA, Knudsen KE. Consequence of the tumor-associated conversion to cyclin D1b. EMBO Mol Med 2016; 7:628-47. [PMID: 25787974 PMCID: PMC4492821 DOI: 10.15252/emmm.201404242] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre-clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant.
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Affiliation(s)
- Michael A Augello
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lisa D Berman-Booty
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Richard Carr
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Akihiro Yoshida
- Medical University of South Carolina, Charleston, SC, USA Hollings Cancer Center, Charleston, SC, USA
| | - Jeffry L Dean
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Matthew J Schiewer
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Felix Y Feng
- Michigan Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA Comprehensive Cancer Center University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Scott A Tomlins
- Michigan Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA Comprehensive Cancer Center University of Michigan Medical Center, Ann Arbor, MI, USA Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Erhe Gao
- Pharmacology & Center for Translational Medicine, Philadelphia, PA, USA
| | - Walter J Koch
- Pharmacology & Center for Translational Medicine, Philadelphia, PA, USA Temple University School of Medicine, Philadelphia, PA, USA
| | - Jeffrey L Benovic
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - John Alan Diehl
- Medical University of South Carolina, Charleston, SC, USA Hollings Cancer Center, Charleston, SC, USA
| | - Karen E Knudsen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA
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26
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Vose JM. Mantle cell lymphoma: 2015 update on diagnosis, risk-stratification, and clinical management. Am J Hematol 2015; 90:739-45. [PMID: 26103436 DOI: 10.1002/ajh.24094] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 06/17/2015] [Indexed: 01/16/2023]
Abstract
DISEASE OVERVIEW Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years. DIAGNOSIS Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION The MCL International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median OS for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group. RISK-ADAPTED THERAPY For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytotoxic regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. In addition, rituximab maintenance therapy may prolong the progression-free survival. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), lenalidamide (anti-angiogenesis) and Ibruitinib (Bruton's Tyrosine Kinase [BTK] inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients. Clinical trials with novel agents are always a consideration for MCL patients.
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Affiliation(s)
- Julie M. Vose
- Division of Hematology/Oncology; University of Nebraska Medical Center; Omaha Nebraska
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27
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Barth MJ, Mavis C, Czuczman MS, Hernandez-Ilizaliturri FJ. Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma. Clin Cancer Res 2015; 21:4391-7. [PMID: 25964296 DOI: 10.1158/1078-0432.ccr-15-0056] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 05/01/2015] [Indexed: 12/12/2022]
Abstract
PURPOSE Mantle cell lymphoma (MCL) is a mature B-cell lymphoma considered to be incurable with current treatments, including first-line rituximab in combination with multiagent chemotherapy and for those eligible, high-dose chemotherapy and stem cell support or rituximab maintenance. On the other hand, achieving a complete remission by high-sensitive flow cytometry is associated with prolonged duration of remission, stressing the need to develop and/or incorporate novel agents into the management of MCL. To this end, we examined the activity of ofatumumab, an anti-CD20 monoclonal antibody with distinct binding and immunologic properties compared to rituximab, in MCL preclinical models. EXPERIMENTAL DESIGN MCL cells were labeled with (51)Cr before incubation with rituximab or ofatumumab (10 μg/mL) plus human serum or effector cells. (51)Cr-release was measured and the percentage of lysis was calculated. Surface CD20, CD55, and CD59 were measured by Imagestream analysis. SCID mice inoculated subcutaneously with Z138 cells were assigned to control versus four doses of ofatumumab or rituximab (10 mg/kg/dose). RESULTS Ofatumumab exhibited enhanced in vitro complement-dependent cytotoxicity activity compared with rituximab in MCL cell lines, despite a high degree of in vitro resistance to rituximab associated with low CD20 levels and/or high expression of complement inhibitory proteins. Ofatumumab also delayed tumor progression and prolonged survival in a murine model of MCL. CONCLUSIONS Our results demonstrate that ofatumumab is more effective than rituximab in MCL preclinical models, including in the presence of rituximab resistance, and support the clinical investigation of ofatumumab in combination with standard systemic chemotherapy in MCL (NCT01527149).
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized
- Antibody-Dependent Cell Cytotoxicity/drug effects
- Antigens, CD20/metabolism
- Antineoplastic Agents/pharmacology
- CD55 Antigens/metabolism
- CD59 Antigens/metabolism
- Cell Line, Tumor
- Complement Activation/drug effects
- Complement Activation/immunology
- Complement System Proteins/immunology
- Cytotoxicity, Immunologic/drug effects
- Disease Models, Animal
- Drug Evaluation, Preclinical
- Drug Resistance, Neoplasm
- Humans
- Lymphoma, Mantle-Cell/drug therapy
- Lymphoma, Mantle-Cell/immunology
- Lymphoma, Mantle-Cell/mortality
- Mice
- Mice, SCID
- Rituximab/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Matthew J Barth
- Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York.
| | - Cory Mavis
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York
| | - Myron S Czuczman
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York
| | - Francisco J Hernandez-Ilizaliturri
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York
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28
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Aleem E, Arceci RJ. Targeting cell cycle regulators in hematologic malignancies. Front Cell Dev Biol 2015; 3:16. [PMID: 25914884 PMCID: PMC4390903 DOI: 10.3389/fcell.2015.00016] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/25/2015] [Indexed: 12/20/2022] Open
Abstract
Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.
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Affiliation(s)
- Eiman Aleem
- Department of Child Health, The Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children's Hospital, University of Arizona College of Medicine-Phoenix Phoenix, AZ, USA ; Department of Zoology, Faculty of Science, Alexandria University Alexandria, Egypt
| | - Robert J Arceci
- Department of Child Health, The Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children's Hospital, University of Arizona College of Medicine-Phoenix Phoenix, AZ, USA
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29
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Peyressatre M, Prével C, Pellerano M, Morris MC. Targeting cyclin-dependent kinases in human cancers: from small molecules to Peptide inhibitors. Cancers (Basel) 2015; 7:179-237. [PMID: 25625291 PMCID: PMC4381256 DOI: 10.3390/cancers7010179] [Citation(s) in RCA: 219] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/12/2015] [Indexed: 12/12/2022] Open
Abstract
Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.
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Affiliation(s)
- Marion Peyressatre
- Institut des Biomolécules Max Mousseron, IBMM-CNRS-UMR5247, 15 Av. Charles Flahault, 34093 Montpellier, France.
| | - Camille Prével
- Institut des Biomolécules Max Mousseron, IBMM-CNRS-UMR5247, 15 Av. Charles Flahault, 34093 Montpellier, France.
| | - Morgan Pellerano
- Institut des Biomolécules Max Mousseron, IBMM-CNRS-UMR5247, 15 Av. Charles Flahault, 34093 Montpellier, France.
| | - May C Morris
- Institut des Biomolécules Max Mousseron, IBMM-CNRS-UMR5247, 15 Av. Charles Flahault, 34093 Montpellier, France.
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30
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De Tullio G, De Fazio V, Sgherza N, Minoia C, Serratì S, Merchionne F, Loseto G, Iacobazzi A, Rana A, Petrillo P, Silvestris N, Iacopino P, Guarini A. Challenges and opportunities of microRNAs in lymphomas. Molecules 2014; 19:14723-81. [PMID: 25232701 PMCID: PMC6271734 DOI: 10.3390/molecules190914723] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 08/22/2014] [Accepted: 08/22/2014] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Consequently their aberrant expression and/or functions are related to pathogenesis of many human diseases including cancers. Haematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate commitment, differentiation, proliferation, and apoptosis of hematopoietic stem cells (HSC). Alterations on this network could affect the normal haematopoiesis, leading to the development of haematological malignancies such as lymphomas. The incidence of lymphomas is rising and a significant proportion of patients are refractory to standard therapies. Accurate diagnosis, prognosis and therapy still require additional markers to be used for diagnostic and prognostic purpose and evaluation of clinical outcome. The dysregulated expression or function of miRNAs in various types of lymphomas has been associated with lymphoma pathogenesis. Indeed, many recent findings suggest that almost all lymphomas seem to have a distinct and specific miRNA profile and some miRNAs are related to therapy resistance or have a distinct kinetics during therapy. MiRNAs are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum where they are highly stable and quantifiable within the diagnostic laboratory at each consultation. Accordingly they could be specific biomarkers for lymphoma diagnosis, as well as useful for evaluating prognosis or disease response to the therapy, especially for evaluation of early relapse detection and for greatly assisting clinical decisions making. Here we summarize the current knowledge on the role of miRNAs in normal and aberrant lymphopoiesis in order to highlight their clinical value as specific diagnosis and prognosis markers of lymphoid malignancies or for prediction of therapy response. Finally, we discuss their controversial therapeutic role and future applications in therapy by modulating miRNA.
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Affiliation(s)
- Giacoma De Tullio
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy.
| | - Vincenza De Fazio
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Nicola Sgherza
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Carla Minoia
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Simona Serratì
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Francesca Merchionne
- Haematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi 72100, Italy
| | - Giacomo Loseto
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Angela Iacobazzi
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Antonello Rana
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Patrizia Petrillo
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Pasquale Iacopino
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
| | - Attilio Guarini
- Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy
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31
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Vose JM. Mantle cell lymphoma: 2013 Update on diagnosis, risk-stratification, and clinical management. Am J Hematol 2013; 88:1082-8. [PMID: 24273091 DOI: 10.1002/ajh.23615] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 10/17/2013] [Indexed: 12/19/2022]
Abstract
DISEASE OVERVIEW Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with a short remission duration to standard therapies and a median overall survival of 4-5 years. DIAGNOSIS Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t(11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION The Mantle Cell Lymphoma International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median overall survival (OS) for the low risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group. RISK-ADAPTED THERAPY For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytarabine containing regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor) or lenalidamide (anti-angiogenesis) are approved agents. Clinical trials with Ibruitinib (Bruton's Tyrosine Kinase inhibitor) or Idelalisib (PI3K inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients.
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Affiliation(s)
- Julie M. Vose
- Division of Hematology/OncologyUniversity of Nebraska Medical CenterOmaha Nebraska
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32
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Zaja F, Federico M, Vitolo U, Zinzani PL. Management of relapsed/refractory mantle cell lymphoma: a review of current therapeutic strategies. Leuk Lymphoma 2013; 55:988-98. [PMID: 23865835 DOI: 10.3109/10428194.2013.825903] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Abstract Despite recent advances in therapeutic strategies, a large proportion of patients with mantle cell lymphoma (MCL) experience progression after first-line treatment. Several attempts have been made to assess the role of different therapies for the treatment of patients with relapsed/refractory mantle cell lymphoma; however, a consensus on the optimal therapeutic strategy for each individual patient has not been reached. Overall, clinical evidence from phase II studies shows that high-dose cytarabine containing regimens, stem cell transplant and different biological agents all have promising activity with acceptable safety profiles. Therefore, these therapies can represent suitable treatment options for patients with relapsed/refractory MCL. Among different biological agents, at present only temsirolimus has been tested in a phase III study. This review considers available evidence on the management of relapsed/refractory MCL as discussed during a consensus meeting on the current treatment strategies for MCL.
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Affiliation(s)
- Francesco Zaja
- Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi", DISM, Azienda Ospedaliero Universitaria S. M. Misericordia , Udine , Italy
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von Hohenstaufen KA, Conconi A, de Campos CP, Franceschetti S, Bertoni F, Margiotta Casaluci G, Stathis A, Ghielmini M, Stussi G, Cavalli F, Gaidano G, Zucca E. Prognostic impact of monocyte count at presentation in mantle cell lymphoma. Br J Haematol 2013; 162:465-73. [PMID: 23808798 DOI: 10.1111/bjh.12409] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 05/02/2013] [Indexed: 11/29/2022]
Abstract
An increased number of circulating monocytes at presentation has recently been associated with shorter survival in Hodgkin lymphoma, follicular lymphoma and diffuse large B cell lymphoma. This study aimed to assess the prognostic impact of the absolute monocyte count (AMC) at diagnosis in mantle cell lymphoma (MCL). AMC at diagnosis was available in 97 MCL cases recorded in the databases of the Oncology Institute of Southern Switzerland in Bellinzona (Switzerland) and the Division of Haematology of the Amedeo Avogadro University of Eastern Piedmont in Novara (Italy). With a median follow up of 7 years, the 5-year overall survival was 29% for patients with AMC >0·50 × 10(9) /l and 62% for patients with AMC ≤0·50 × 10(9) /l (P = 0·008). Elevated AMC and beta-2 microglobulin at diagnosis remained independent outcome predictors at multivariate analysis, controlling for the MCL International Prognostic Index (MIPI), and have been used to build a simple prognostic scoring system. In this relatively small and heterogeneous series an increased AMC identified poor-risk patients. Our results suggest that AMC together with the beta-2 microglobulin level might provide an inexpensive way to stratify MCL patient risk as a complement to the MIPI, which was confirmed to be a very powerful prognostic tool.
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34
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Fang C, Dong HJ, Zou ZJ, Fan L, Wang L, Zhang R, Xu J, Xu W, Li JY. High expression of cyclic nucleotide phosphodiesterase 7B mRNA predicts poor prognosis in mantle cell lymphoma. Leuk Res 2013; 37:536-40. [DOI: 10.1016/j.leukres.2013.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 01/30/2013] [Accepted: 02/05/2013] [Indexed: 12/20/2022]
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35
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Conconi A, Franceschetti S, Lobetti-Bodoni C, Stathis A, Margiotta-Casaluci G, Ramponi A, Mazzucchelli L, Bertoni F, Ghielmini M, Gaidano G, Cavalli F, Zucca E. Risk factors of central nervous system relapse in mantle cell lymphoma. Leuk Lymphoma 2013; 54:1908-14. [DOI: 10.3109/10428194.2013.767454] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Sagaert X, Tousseyn T, Yantiss RK. Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology. World J Gastrointest Oncol 2012; 4:238-49. [PMID: 23443141 PMCID: PMC3581849 DOI: 10.4251/wjgo.v4.i12.238] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 08/29/2012] [Accepted: 11/20/2012] [Indexed: 02/05/2023] Open
Abstract
The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.
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Affiliation(s)
- Xavier Sagaert
- Xavier Sagaert, Thomas Tousseyn, Department of Pathology University Hospitals Leuven, B-3000 Leuven, Belgium
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37
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Jung HJ, Chen Z, McCarty N. Synergistic anticancer effects of arsenic trioxide with bortezomib in mantle cell lymphoma. Am J Hematol 2012; 87:1057-64. [PMID: 22965904 DOI: 10.1002/ajh.23317] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Revised: 06/28/2012] [Accepted: 07/18/2012] [Indexed: 12/12/2022]
Abstract
Mantle cell lymphoma (MCL) is a subtype of B-cell Non-Hodgkin's Lymphoma (NHL) and accounts for ~6% of all lymphomas. MCL is highly refractory to most chemotherapy including newer antibody-based therapeutic approaches, and high-grade MCL has one of the worst survival rates among NHLs. Therefore, the development of new therapeutic strategies to overcome drug resistance of MCL is important. In this article, we tested the effects of arsenic trioxide (As(2) O(3) , ATO) in bortezomib-resistant MCL. ATO is reported to induce complete remission in the patients with relapsed or refractory acute promyelocytic leukemia. Their effects in MCL, however, have not been explored. In this report, we show that ATO effectively inhibited the growth of MCL cells in vitro. ATO treatment also reduced cyclin D1 expression which is a genetic hallmark of MCL and NF-kB expression which was reported to have a prosurvival role in some MCL cells. The induction of apoptosis in MCL was partially due to reduced levels of cyclin D1 and increased levels of apoptosis-related molecules. The antiproliferative effects of bortezomib on MCL greatly increased when the cells were also treated with ATO, indicating ATO can sensitize MCL to bortezomib. Similar results were noted in bortezomib-resistant cell lines. In conclusion, ATO may be an alternative drug for use in combined adjuvant therapies for MCL, and further clinical testing should be performed.
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Affiliation(s)
- Hyun Joo Jung
- Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM) University of Texas-Health Science Center at Houston, Houston, TX 77030, USA
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Abstract
Small B cell lymphoma is a morphological designation to a group of B cell lymphomas which are composed of a clonal population of small lymphoid cells. The subtypes of this category have diagnostically distinct characteristics and different clinical behaviors and treatment. Correct diagnosis and classification of these subsets depend on the integration of morphologic, immunophenotypic, and molecular genetic features. In this paper, differential diagnosis of this category of tumors and a practical approach based on biomarker evaluation are discussed.
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Prasad A, Shrivastava A, Papadopoulos E, Kuzontkoski PM, Reddy MVR, Gillum AM, Kumar R, Reddy EP, Groopman JE. Combined administration of rituximab and on 013105 induces apoptosis in mantle cell lymphoma cells and reduces tumor burden in a mouse model of mantle cell lymphoma. Clin Cancer Res 2012; 19:85-95. [PMID: 23124440 DOI: 10.1158/1078-0432.ccr-12-1425] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma, and new therapeutic strategies are urgently needed. EXPERIMENTAL DESIGN The effects of ON 013105, a novel benzylstyryl sulfone kinase inhibitor, alone or with doxorubicin or rituximab, were examined in Granta 519 and Z138C cells. For in vivo studies, CB17/SCID mice were implanted subcutaneously with Z138C cells and treated with various combinations of ON 013105, doxorubicin, and rituximab. Tumor burden and body weight were monitored for 28 days. RESULTS ON 013105 induced mitochondria-mediated apoptosis in MCL cells. Death was preceded by translocation of tBid to the mitochondria and cytochrome c release. In addition, ON 013105-treated cells exhibited reduced levels of cyclin D1, c-Myc, Mcl-1, and Bcl-xL. Using nuclear magnetic resonance (NMR) spectroscopy, we showed specific binding of ON 013105 to eIF4E, a critical factor for the initiation of protein translation. We proffer that this drug-protein interaction preferentially prevents the translation of the aforementioned proteins and may be the mechanism by which ON 013105 induces apoptosis in MCL cells. Efficacy studies in a mouse xenograft model showed that ON 013105 inhibited MCL tumor growth and that combining ON 013105 with rituximab reduced tumor burden further with negligible unwanted effects. CONCLUSIONS Our findings suggest that ON 013105, alone or in combination with rituximab, may be a potent therapeutic agent to treat MCLs.
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Affiliation(s)
- Anil Prasad
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Abstract
The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G1 phase when the cell prepares to initiate DNA synthesis. Although CDK4-null mutant mice are viable and cell proliferation is not significantly affected in vitro due to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development, and tumorigenesis as well as how small molecule inhibitors of CDK4 can be used to treat disease.
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41
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Cander S, Ertürk E, Karkucak M, Oz Gül O, Görükmez O, Yakut T, Unal OK, Ersoy C, Tuncel E, Imamoğlu S. Effect of cyclin [corrected] D1 (CCND1) gene polymorphism on tumor formation and behavior in patients with prolactinoma. Gene 2012; 509:158-63. [PMID: 22967707 DOI: 10.1016/j.gene.2012.07.056] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 07/30/2012] [Indexed: 11/16/2022]
Abstract
The objective of this study was to investigate the effect of G870A gene polymorphism of CCND1 on the formation and behavioral features of prolactinomas. One hundred and thirteen patients with prolactinoma and 108 age and gender matched control were included in the study. The patients were divided into two groups as noninvasive and invasive tumors. CCND1 G870A gene polymorphism was compared in patients/control and invasive/noninvasive groups. A and G allele frequencies were found as 41.7% and 58.3% in the controls, and 61.1% and 38.9% in the patients (p<0.01). Rates of G/G, G/A and A/A genotypes were found as 11.8%, 55.9% and 32.4% in the noninvasive group, and 15.6%, 44.4% and 40.0% in the invasive group, respectively. Differences between patient and control groups were significant but were not between invasive and noninvasive groups in terms of the allele frequencies and genotype distribution. Mean tumor size and serum levels of prolactin at the time of diagnosis and change in these values after the treatment were not found statistically significant in genotype subgroups. CCND1 G870A gene polymorphism may be an important factor in the early stages of the tumor formation. However, it did not affect the features of the tumor.
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Affiliation(s)
- Soner Cander
- Uludag University, Medical School, Department of Endocrinology and Metabolism, Bursa, Turkey.
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42
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Aquino G, Franco R, Ronconi F, Anniciello A, Russo L, De Chiara A, Panico L. Peripheral T-cell Lymphoma with Cyclin D1 overexpression: a case report. Diagn Pathol 2012; 7:79. [PMID: 22770229 PMCID: PMC3475098 DOI: 10.1186/1746-1596-7-79] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 05/21/2012] [Indexed: 11/30/2022] Open
Abstract
Peripheral T-cell lymphomas not otherwise specified are generally considered aggressive non-Hodgkin lymphomas, because of poor natural outcome and response to therapy. They show a complex karyotype without any specific genetic hallmark. We report a case of peripheral T-cell lymphoma not otherwise specified with heterogeneous nuclear Cyclin D1 immunohistochemical overexpression, due to gene copy gain, a phenomenon similar to that observed in Mantle Cell Lymphoma characterized by t(11;14)(q13;q32). In this case report we underline the diagnostic pitfall rapresented by Cyclin D1 immunoistochemical overexpression in a T-cell lymphoma. Several pitfalls could lead to misinterpretation of diagnosis, therefore, we underlined the need to integrate the classical histology and immunohistochemistry with molecular tests as clonality or Fluorescence in situ hybridization.
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Affiliation(s)
- Gabriella Aquino
- Pathology Unit, National Cancer Institute Fondazione Giovanni Pascale, Via Mariano Semmola, 80131 Napoli, Italy
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43
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Vose JM. Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management. Am J Hematol 2012; 87:604-9. [PMID: 22615102 DOI: 10.1002/ajh.23176] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
DISEASE OVERVIEW Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with a short remission duration to standard therapies and a median overall survival of 4-5 years. DIAGNOSIS Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t(11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION The mantle cell lymphoma international prognostic index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median overall survival (OS) for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 and 29 months for the high-risk group. RISK-ADAPTED THERAPY For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytarabine containing regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), BTK inhibitors or CAL-101 (B-cell receptor inhibitors) or lenalidamide (antiangiogenesis) have clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients.
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MESH Headings
- Adult
- Aged
- Antibodies, Monoclonal, Murine-Derived/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Asymptomatic Diseases
- Biomarkers, Tumor/analysis
- Bone Marrow Examination
- Chemoradiotherapy
- Chromosomes, Human, Pair 11/ultrastructure
- Chromosomes, Human, Pair 14/ultrastructure
- Combined Modality Therapy
- Cyclophosphamide/administration & dosage
- Cytarabine/administration & dosage
- Dexamethasone/administration & dosage
- Disease Management
- Doxorubicin/administration & dosage
- Female
- Genes, bcl-1
- Humans
- Lymphoma, Mantle-Cell/diagnosis
- Lymphoma, Mantle-Cell/epidemiology
- Lymphoma, Mantle-Cell/genetics
- Lymphoma, Mantle-Cell/therapy
- Male
- Methotrexate/administration & dosage
- Middle Aged
- Multicenter Studies as Topic
- Randomized Controlled Trials as Topic
- Risk Assessment
- Rituximab
- Salvage Therapy
- Stem Cell Transplantation
- Translocation, Genetic
- Vincristine/administration & dosage
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Affiliation(s)
- Julie M Vose
- Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE 68198-7680, USA.
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44
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Hegde GV, Nordgren TM, Munger CM, Mittal AK, Bierman PJ, Weisenburger DD, Vose JM, Sharp JG, Joshi SS. Novel therapy for therapy-resistant mantle cell lymphoma: multipronged approach with targeting of hedgehog signaling. Int J Cancer 2012; 131:2951-60. [PMID: 22511234 DOI: 10.1002/ijc.27602] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Accepted: 03/22/2012] [Indexed: 01/01/2023]
Abstract
Mantle cell lymphoma (MCL) is one of the most aggressive B-cell lymphomas with a median patient survival of only 5-7 years. The failure of existing therapies is mainly due to disease relapse when therapy-resistant tumor cells remain after chemotherapy. Therefore, development and testing of novel therapeutic strategies to target these therapy-resistant MCL are needed. Here, we developed an in vivo model of therapy-resistant MCL by transplanting a patient-derived MCL cell line (Granta 519) into NOD/SCID mice followed by treatment with combination chemotherapy. Cytomorphologic, immunophenotypic, in vitro and in vivo growth analyses of these therapy-resistant MCL cells confirm their MCL origin and resistance to chemotherapy. Moreover, quantitative real-time PCR revealed the upregulation of GLI transcription factors, which are mediators of the hedgehog signaling pathway, in these therapy-resistant MCL cells. Therefore, we developed an effective therapeutic strategy for resistant MCL by treating the NOD/SCID mice bearing Granta 519 MCL with CHOP chemotherapy to reduce tumor burden combined with GLI-antisense oligonucleotides or bortezomib, a proteosome inhibitor, to target therapy-resistant MCL cells that remained after chemotherapy. This regimen was followed by treatment with MCL-specific cytotoxic T lymphocytes to eliminate all detectable leftover minimal residual disease. Mice treated with this strategy showed a significantly increased survival and decreased tumor burden compared to the mice in all other groups. Such therapeutic strategies that combine chemotherapy with targeted therapy followed by tumor-specific immunotherapy are effective and have excellent potential for clinical application to provide long-term, disease-free survival in MCL patients.
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Affiliation(s)
- Ganapati V Hegde
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-6395, USA
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45
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Dawar R, Hernandez-Ilizaliturri F. The emerging role of lenalidomide in the management of mantle cell lymphoma (MCL). Best Pract Res Clin Haematol 2012; 25:185-90. [PMID: 22687454 DOI: 10.1016/j.beha.2012.04.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Mantle cell lymphoma (MCL) is considered an aggressive and incurable B-cell malignancy despite current available treatments that include the incorporation of rituximab, bortezomib, high-dose cytarabine, and for those eligible, high dose chemotherapy and autologous bone marrow transplant (HDC-ASCT). Patients with relapsed/refractory MCL represent a challenge for the treating physician stressing the need to develop therapeutic agents. Lenalidomide, a novel inmmunomodulatory drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory B-cell lymphoma. Biologically, the mechanisms responsible for lenalidomide activity are yet to be clearly defined. Based on pre-clinical models and early correlative studies conducted parallel to clinical trials, lenalidomide has been found to enhance NK-cell and T-cell activity against tumor cells, alter the balance of pro- and anti-inflammatory cytokines in the tumor bed, inhibit angiogenesis, and to a lesser degree, induce cell cycle arrest and apoptosis in cancer cells. Together, all these biological effects appear to play a role in the activity observed in lymphoma patients treated with lenalidomide. Given the effect in NK- and T-cell function, lenalidomide is an alternative strategy to enhance the anti-tumor activity of monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), and MCL. The favorable toxicity profile and route of administration made the use of lenalidomide an attractive therapy for certain types of patients (i.e. elderly, chemotherapy unfit, etc.). The erratic but serious incidence of tumor lysis syndrome and/or tumor flare reactions provides challenges in the incorporation of lenalidomide in the management of previously untreated lymphoma patients with bulky adenopathy. Early studies evaluating the efficacy and toxicity of lenalidomide in combination with steroids or rituximab/bendamustine in MCL are promising and warrant further study. In addition, the evaluation of lenalidomide in the maintenance setting (i.e. post HDC-ASCT) or in combination with other target specific agents (i.e. proteasome inhibitors) in MCL is being addressed in ongoing clinical trials. We provide a general overview of the clinical development of lenalidomide in MCL. Future translational and clinical studies will further define the role of lenalidomide in the management of de novo or relapsed/refractory MCL and may assist in the identification of subset of MCL patients most likely to gain clinical benefit from this exiting agent.
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Affiliation(s)
- Richa Dawar
- Medical Oncology and Immunology, Roswell Park Cancer Institute (RPCI), Elm and Carlton Streets, Buffalo, NY 14263, USA
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46
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Estella-Hermoso de Mendoza A, Campanero MA, Lana H, Villa-Pulgarin JA, de la Iglesia-Vicente J, Mollinedo F, Blanco-Prieto MJ. Complete inhibition of extranodal dissemination of lymphoma by edelfosine-loaded lipid nanoparticles. Nanomedicine (Lond) 2012; 7:679-90. [DOI: 10.2217/nnm.11.134] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Lipid nanoparticles (LNs) made of synthetic lipids Compritol® 888 ATO and Precirol® ATO 5 were developed with an average size of 110.4 ± 2.1 and 103.1 ± 2.9 nm, and an encapsulation efficiency above 85% for both type of lipids. These LNs decrease the hemolytic toxicity of the drug by 90%. Materials & methods: Pharmacokinetic and biodistribution profiles of the drug were studied after intravenous and oral administration of edelfosine-containing LNs. Results: This provided an increase in relative oral bioavailability of 1500% after a single oral administration of drug-loaded LNs, maintaining edelfosine plasma levels over 7 days in contrast to a single oral administration of edelfosine solution, which presented a relative oral bioavailability of 10%. Moreover, edelfosine-loaded LNs showed a high accumulation of the drug in lymph nodes and resulted in slower tumor growth than the free drug in a murine lymphoma xenograft model, as well as potent extranodal dissemination inhibition. Original submitted 5 April 2011; Revised submitted 5 July 2011
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Affiliation(s)
| | - Miguel A Campanero
- Clinical Pharmacology Service, University of Navarra Clinic, E-31008, Spain
| | - Hugo Lana
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, E-31008, Spain
| | - Janny A Villa-Pulgarin
- Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain
| | - Janis de la Iglesia-Vicente
- Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain
| | - Faustino Mollinedo
- Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain
| | - María J Blanco-Prieto
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, E-31008, Spain
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47
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The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma. Ann Hematol 2012; 91:847-56. [PMID: 22231280 DOI: 10.1007/s00277-011-1377-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 11/19/2011] [Indexed: 01/05/2023]
Abstract
Single-agent bortezomib, a potent, selective, and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the MCL patients; however, complete remission rates are low and duration of response proved to be relatively short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Rational combination treatment and schedules require profound knowledge of underlying molecular mechanisms. Here we show that single-agent bortezomib treatment of MCL cell lines leads to G2/M arrest and induction of apoptosis accompanied by downregulation of EIF4E and CCND1 mRNA but upregulation of p15(INK4B) and p21 mRNA. We further present synergistic efficacy of bortezomib combined with cytarabine in MCL cell lines. Interestingly this sequence-dependent synergistic effect was seen almost exclusively in combination with AraC, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.
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48
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Edlefsen KL, Greisman HA, Yi HS, Mantei KM, Fromm JR. Early lymph node involvement by mantle cell lymphoma limited to the germinal center: report of a case with a novel "follicular in situ" growth pattern. Am J Clin Pathol 2011; 136:276-81. [PMID: 21757601 DOI: 10.1309/ajcp6kffgtc8plvr] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Recently, several reports have described cases of "in situ" mantle cell lymphoma (MCL) in which scattered cyclin D1+ cells were present within the mantle zones of reactive-appearing lymphoid follicles. In this report, we describe an unusual histologic pattern of in situ MCL that was identified in a staging lymph node for colonic adenocarcinoma resected 4 years before a diagnosis of symptomatic MCL. Retrospective immunohistochemical studies showed scattered cyclin D1-expressing cells within otherwise reactive germinal centers but not in the surrounding mantle zones. The presence of early MCL cells limited to reactive germinal centers represents a novel "follicular in situ" growth pattern for MCL, which overlaps morphologically with reactive follicular hyperplasia and follicular lymphoma and which could have implications for MCL pathogenesis.
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49
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Tiemann K, Alluin JV, Honegger A, Chomchan P, Gaur S, Yun Y, Forman SJ, Rossi JJ, Chen RW. Small interfering RNAs targeting cyclin D1 and cyclin D2 enhance the cytotoxicity of chemotherapeutic agents in mantle cell lymphoma cell lines. Leuk Lymphoma 2011; 52:2148-54. [PMID: 21745168 DOI: 10.3109/10428194.2011.593272] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Cyclin D1 (CCND1) is a known cell cycle regulator whose overexpression is a hallmark of mantle cell lymphoma (MCL). Although molecular techniques have unified the diagnostic approach to MCL, no therapeutic advances have been made to target this particular pathway. The significance of CCND1 in the pathogenesis and treatment of MCL has yet to be defined. We have taken advantage of RNA interference (RNAi) to down-regulate CCND1 expression in two MCL cell lines (Granta-519 and Jeko-1) to investigate the cytotoxic effect of combining RNAi with conventional chemotherapeutic agents. We designed four small interfering RNAs (siRNAs) specific to CCND1, one specific to CCND2, and one dual-targeting siRNA that simultaneously down-regulates CCND1 and CCND2. Etoposide and doxorubicin were used as chemotherapeutics in combination with the siRNAs. The transfected siRNAs in MCL cell lines triggered 40-60% reduction in target mRNA and protein levels. Importantly, the siRNA-mediated reduction in cyclins resulted in decreased IC(50) (50% inhibitory concentration) values for both doxorubicin and etoposide. The combination of siRNA-mediated inhibition of the cyclins along with chemotherapeutic agents could potentially be used to lower the effective doses of the chemotherapeutic agents and reduce drug-related toxicities.
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Affiliation(s)
- Katrin Tiemann
- Division of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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50
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Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011; 11:558-72. [PMID: 21734724 DOI: 10.1038/nrc3090] [Citation(s) in RCA: 1044] [Impact Index Per Article: 74.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Cyclin D1, and to a lesser extent the other D-type cyclins, is frequently deregulated in cancer and is a biomarker of cancer phenotype and disease progression. The ability of these cyclins to activate the cyclin-dependent kinases (CDKs) CDK4 and CDK6 is the most extensively documented mechanism for their oncogenic actions and provides an attractive therapeutic target. Is this an effective means of targeting the cyclin D oncogenes, and how might the patient subgroups that are most likely to benefit be identified?
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Affiliation(s)
- Elizabeth A Musgrove
- Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney NSW 2010, Australia
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