Our current research mainly focuses on the identification and characterization of novel mutations and epigenetic alterations of tumor suppressor genes or oncogenes in lymphoid cancers. Our interest mainly resides in lymphomas (e.g. follicular lymphoma) and other lymphoid cancers (e.g. multiple myeloma) which are neoplastic diseases having a high degree of genetic heterogeneity.
We frequently use next generation sequencing (NGS) based technologies (e.g. WES, RNA-Seq, targeted NGS) to generate a candidate list of aberrant genes using panels of lymphoma patient samples. We then cross-validate mutations that are identified through NGS methodologies by applying Sanger sequencing. Moreover, our studies focus on genome-wide or loci-specific methylation changes in cancer samples. Altogether, we characterize these aberrations using a combination of genetic, epigenetic and molecular biology assays. In general, our studies follow a wholistic approach which involves the cooperation of a variety interrelated biomedical disciplines such as pathology, functional genomics, and computational bioinformatics. Our eventual goal is to identify and characterize genetic and epigenetic abnormalities in individual cancer patients to translate the discoveries as personalized medicine.
IL2 signaling plays a crucial role during NK cell activation including proliferation as a response to virus-infected cells or neoplastic cells. Appropriate termination of IL2 signaling is required to control NK cell expansion and prevent NK cell malignancies. The molecular mechanisms responsible for termination of IL2 signaling were largely unknown. An international collaborative study from Dr. Küçük’s research group revealed that PRDM1 decreases sensitivity of NK cells to IL2 cytokine through direct transcriptional inhibition of IL2RA, thereby preventing uncontrolled NK cell expansion.
From Lymphoid Cancer Genomics Research Group Dr. Burcu Akman, Dr. Xiaozhou Hu, Tevfik Hatipoğlu, and Dr. Can Küçük contributed to this study, which has been highlighted in the recent issue of the Journal of Leukocyte Biology. For more information, please see the following link: https://jlb.onlinelibrary.wiley.com/
Wang Y, Ba HJ, Wen XZ, Zhou M, Küçük C, Tamagnone L, Wei L, You H. A prognostic model for melanoma patients on the basis of immune-related lncRNAs.. Aging. 2021 March ; 13 . doi:10.18632/aging.202730.
Küçük C. Genetic susceptibility to natural killer T-cell lymphoma.. The Lancet. Oncology. 2020 February ; 21 (2) : 196-197. doi:10.1016/S1470-2045(19)30820-4.
Esmeray E, Küçük C. Genetic alterations in B cell lymphoma subtypes as potential biomarkers for noninvasive diagnosis, prognosis, therapy, and disease monitoring.. Turkish journal of biology = Turk biyoloji dergisi. 2020 February ; 44 (1) : 1-14. doi:10.3906/biy-1908-23.
Akman B, Hu X, Liu X, Hatipoğlu T, You H, Chan WC, Küçük C. PRDM1 decreases sensitivity of human NK cells to IL2-induced cell expansion by directly repressing CD25 (IL2RA).. Journal of leukocyte biology. 2020 November . doi:10.1002/JLB.2A0520-321RR.
Küçük C, Wei L, You H. Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy.. Frontiers in oncology. 2020 August ; 10 : 1276. doi:10.3389/fonc.2020.01276.
Küçük C, Wang J, Xiang Y, You H. Epigenetic aberrations in natural killer/T-cell lymphoma: diagnostic, prognostic and therapeutic implications.. Therapeutic advances in medical oncology. 2020 February ; 12 : 1758835919900856. doi:10.1177/1758835919900856.
Kursun, Deniz; Kucuk, Can. Systematic analysis of the frequently amplified 2p15-p16.1 locus reveals PAPOLG as a potential proto-oncogene in follicular and transformed follicular lymphoma. TURKISH JOURNAL OF BIOLOGY. 2019 ; 43 (2) . doi:10.3906/biy-1810-2.
Wan Y, He D, Ye Y, Zhang W, Zhao S, Long Y, Chen M, Küçük C. Primary cardiac diffuse large B-cell lymphoma with concurrent high MYC and BCL2 expression in an immunocompetent Chinese elderly woman. Cardiovasc Pathol. 2017 November ; 31 : 54-56. doi:10.1016/j.carpath.2017.07.006.
Hu X, Baytak E, Li J, Akman B, Okay K, Hu G, Scuto A, Zhang W, Küçük C. The relationship of REL proto-oncogene to pathobiology and chemoresistance in follicular and transformed follicular lymphoma. Leuk Res. 2017 March ; 54 : 30-38. doi:10.1016/j.leukres.2017.01.001.
Baytak E, Gong Q, Akman B, Yuan H, Chan WC, Küçük C. Whole transcriptome analysis reveals dysregulated oncogenic lncRNAs in natural killer/T-cell lymphoma and establishes MIR155HG as a target of PRDM1.. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2017 May ; 39 (5) : 1010428317701648. doi:10.1177/1010428317701648.
Gao, Li-Min; Zhao, Sha; Liu, Wei-Ping; Zhang, Wen-Yan; Li, Gan-Di; Kucuk, Can; Hu, Xiao-Zhou; Chan, Wing C.; Tang, Yuan; Ding, Wen-Shuang; Yan, Jia-Qi; Yao, Wen-Qing; Wang, Jian Chao. Clinicopathologic Characterization of Aggressive Natural Killer Cell Leukemia Involving Different Tissue Sites. AMERICAN JOURNAL OF SURGICAL PATHOLOGY. 2016 June ; 40 (6) : 836-846. doi:10.1097/PAS.0000000000000634.
Kucuk, Can; Hu, Xiaozhou; Gong, Qiang; Jiang, Bei; Cornish, Adam; Gaulard, Philippe; McKeithan, Timothy; Chan, Wing C.. Diagnostic and Biological Significance of KIR Expression Profile Determined by RNA-Seq in Natural Killer/T-Cell Lymphoma. AMERICAN JOURNAL OF PATHOLOGY. 2016 June ; 186 (6) : 1435-1441. doi:10.1016/j.ajpath.2016.02.011.
Hu X, Chan WC, Kücük C. Generation of a genetically engineered aggressive nk-cell leukemia cell line with stable IL2 expression. Acta Medica International. 2015 July ; 2 (2) : 78-84. doi:10.5530/ami.2015.3.6.
Küçük C, Jiang B, Hu X, Zhang W, Chan JK, Xiao W, Lack N, Alkan C, Williams JC, Avery KN, Kavak P, Scuto A, Sen E, Gaulard P, Staudt L, Iqbal J, Zhang W, Cornish A, Gong Q, Yang Q, Sun H, d'Amore F, Leppä S, Liu W, Fu K, de Leval L, McKeithan T, Chan WC. Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells.. Nature communications. 2015 January ; 6 : 6025. doi:10.1038/ncomms7025.
Küçük C, Hu X, Jiang B, Klinkebiel D, Geng H, Gong Q, Bouska A, Iqbal J, Gaulard P, McKeithan TW, Chan WC. Global promoter methylation analysis reveals novel candidate tumor suppressor genes in natural killer cell lymphoma.. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 April ; 21 (7) : 1699-711. doi:10.1158/1078-0432.CCR-14-1216.
Bouska A, McKeithan TW, Deffenbacher KE, Lachel C, Wright GW, Iqbal J, Smith LM, Zhang W, Kucuk C, Rinaldi A, Bertoni F, Fitzgibbon J, Fu K, Weisenburger DD, Greiner TC, Dave BJ, Gascoyne RD, Rosenwald A, Ott G, Campo E, Rimsza LM, Delabie J, Jaffe ES, Braziel RM, Connors JM, Staudt LM, Chan WC. Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma.. Blood. 2014 March ; 123 (11) : 1681-90. doi:10.1182/blood-2013-05-500595.
Küçük C, Hu X, Iqbal J, Gaulard P, Klinkebiel D, Cornish A, Dave BJ, Chan WC. HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms.. The American journal of pathology. 2013 January ; 182 (1) : 49-55. doi:10.1016/j.ajpath.2012.09.012.
Perry AM, Warnke RA, Hu Q, Gaulard P, Copie-Bergman C, Alkan S, Wang HY, Cheng JX, Bacon CM, Delabie J, Ranheim E, Kucuk C, Hu X, Weisenburger DD, Jaffe ES, Chan WC. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.. Blood. 2013 November ; 122 (22) : 3599-606. doi:10.1182/blood-2013-07-512830.
Liu C, Iqbal J, Teruya-Feldstein J, Shen Y, Dabrowska MJ, Dybkaer K, Lim MS, Piva R, Barreca A, Pellegrino E, Spaccarotella E, Lachel CM, Kucuk C, Jiang CS, Hu X, Bhagavathi S, Greiner TC, Weisenburger DD, Aoun P, Perkins SL, McKeithan TW, Inghirami G, Chan WC. MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma.. Blood. 2013 September ; 122 (12) : 2083-92. doi:10.1182/blood-2012-08-447375.
Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, Parrens M, Martin A, Xerri L, Brousset P, Chan LC, Chan WC, Gaulard P, Mak TW. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma.. Blood. 2012 February ; 119 (8) : 1901-3. doi:10.1182/blood-2011-11-391748.
Küçük C, Iqbal J, Hu X, Gaulard P, De Leval L, Srivastava G, Au WY, McKeithan TW, Chan WC. PRDM1 is a tumor suppressor gene in natural killer cell malignancies.. Proceedings of the National Academy of Sciences of the United States of America. 2011 December ; 108 (50) : 20119-24. doi:10.1073/pnas.1115128108.
Iqbal J, Weisenburger DD, Chowdhury A, Tsai MY, Srivastava G, Greiner TC, Kucuk C, Deffenbacher K, Vose J, Smith L, Au WY, Nakamura S, Seto M, Delabie J, Berger F, Loong F, Ko YH, Sng I, Liu X, Loughran TP, Armitage J, Chan WC, International Peripheral T-cell Lymphoma Project.. Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro.. Leukemia. 2011 February ; 25 (2) : 348-58. doi:10.1038/leu.2010.255.
Iqbal J, Kucuk C, Deleeuw RJ, Srivastava G, Tam W, Geng H, Klinkebiel D, Christman JK, Patel K, Cao K, Shen L, Dybkaer K, Tsui IF, Ali H, Shimizu N, Au WY, Lam WL, Chan WC. Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies.. Leukemia. 2009 June ; 23 (6) : 1139-51. doi:10.1038/leu.2009.3.
Total : 23
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : REL Onkogeninin Foliküler Lenfoma Oluşumundaki Rolünün İncelenmesi, Finished