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DEPARTMENT OF IMMUNOLOGY & MICROBIOLOGY, A Leader in Immunology, Microbiology and Microbial Pathogenesis Research and Training

Immunology and Microbiology
 

Jing Hong Wang, M.D., Ph.D.

Assistant Professor of Immunology & Microbiology


12800 E. 19th Ave., RC1N-9100
Mail Stop 8333, Aurora, CO 80045

Phone: 303-724-8673
Lab: 303-724-8704
E-mail: jing.wang@ucdenver.edu

Genomic instability and cancer development: Internal or external insults can cause breakages of chromosomes. Incorrect juxtaposition of different pieces of chromosomes during the repair process leads to chromosomal translocation. It is widely accepted that chromosomal translocation can promote cancer development by disrupting tumor suppressors, activating oncogenes, or generating aberrant fusion proteins. Furthermore, cancer type-specific chromosomal translocations are frequently identified in leukemia and lymphomas, and increasingly found in solid tumors. However, many aspects of the mechanisms underlying the generation and cancer-type specificity of chromosomal translocations are poorly understood.  The goal of our laboratory is to understand the molecular mechanisms that promote chromosomal translocations and cancer development in B lymphocytes. Our primary approaches are to establish specific mouse models that resemble human mature B cell lymphomas. In particular, we focus on DNA double strand breaks (DSBs) response factors. These proteins are essential for properly repairing DSBs. In the absence of these factors, DSBs will separate and progress into chromosomal breaks and translocations. We are investigating how these proteins suppress oncogenic translocations. Furthermore, we are elucidating how cancer-type specific translocations are generated at the molecular level, and how mechanistic factors including DSB frequency, spatial proximity of target loci and DNA repair pathways influence translocation frequency and spectrum. We will also employ novel genome-editing approaches (CRISPR-Cas9 system) to test how genetic alterations in DNA repair influence the level of on-going genomic instability in cancer cells.


Molecular mechanism of somatic hypermutation and class switch recombination: More than 90% of human lymphomas are B cell-derived. This is likely because B cells extensively shuffle their genomic DNA during immune responses. Upon immunizations and infections, activated B cells form a specialized structure termed germinal center (GC). In the GC, two B cell-specific DNA alterations occur, namely somatic hypermutation (SHM) and class switch recombination (CSR). Both SHM and CSR rely on the activity of an enzyme called activation induced deaminase (AID). In activated B lymphocytes, AID causes point mutations in the variable regions of the immunoglobulin (Ig) genes. These mutations cause small changes in the protein sequence of antibodies and lead to increased antibody affinity for specific antigens. AID also induces DSBs in the repetitive switch regions that lie upstream of each constant region exon of the Ig heavy chain locus to mediate CSR.  CSR assigns antigen-appropriate effector functions to antibody molecules and is, therefore, a process important for productive immune responses against pathogens.  Eventually AID-mediated DNA alterations enhance antibody diversity and specificity. Given that AID is a potent DNA mutator, its activity has to be tightly regulated. We are interested in elucidating the molecular mechanisms that regulate AID targeting specificity and efficiency. Furthermore, we are also investigating how AID contributes to genomic instability and cancer development. Lastly, we expand our research into the signaling control of CSR process. In particular, we are investigating how antigens and co-stimulatory molecules cooperatively stimulate CSR and elucidating the signaling transduction pathways that promote or inhibit CSR.

Peer-reviewed Publications:
  • Chen Z, Ranganath S, Viboolsittiseri SS, Eder MD, Chen X, Elos MT, Yuan S, Hansen E, Wang JH (2014). AID-Initiated DNA Lesions Are Differentially Processed in Distinct B cell Populations. Journal of Immunology, in press
  • Chen Z and Wang JH (2014). Generation and Repair of AID-initiated DNA Lesions in B Lymphocytes. Front Med. 2014 Jun;8(2):201-16. doi: 10.1007/s11684-014-0324-4. Epub 2014 Apr 21.
  • Lu Y, Wu Y, Feng X, Shen R, Wang JH, Fallahi M, Li W, Yang C, Hankey W, Li MO, Cleveland JL and Zou X. Cdk4 deficiency augments Myc-driven lymphomagenesis via a Foxo1-Rag1/Rag2 pathway that provokes genomic instability. Journal of Clinical Investigation, 2014 Apr 1;124(4):1672-84. doi: 10.1172/JCI63139. Epub 2014 Mar 10.
  • Hosomi S, Chen Z*, Baker K, Chen L, Huang YH, Olszak T, Zeissig S, Wang JH, Mandelboim O, Beauchemin N, Lanier LL, Blumberg RS. CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling. Eur J Immunol, 2013 May 22. doi: 10.1002/eji.201242676. [Epub ahead of print]PMID: 23696226. *Equal contribution to the work.
  • Chen Z, Yan CT, Dou Y, Viboolsittiseri SS, Wang JH (2013). The Role of a Newly Identified SET Domain-Containing Protein, SETD3, in Oncogenesis. Haematologica, 2013 May;98(5):739-43. PMID: 23065515 [PubMed - in process] PMCID: PMC3640118
  • Chen Z, Viboolsittiseri SS, O’Connor BP, Wang JH (2012). Target DNA Sequence Directly Regulates the Frequency of AID-Dependent Mutations. Journal of Immunology, Oct 15;189(8):3970-82. PMID: 22962683
  • Wang JH (2012). Mechanisms and impacts of chromosomal translocations in cancers. Frontiers of Medicine, 2012;(3):263-74. Epub 2012 Aug 4. PMID: 22865120.
  • Boboila C, Oksenych V, Gostissa M, Wang JH, Zha S, Zhang Y, Chai H, Lee CS, Jankovic M, Saez LM, Nussenzweig MC, McKinnon PJ, Alt FW, Schwer B (2012). Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1). Proc. Natl. Acad. Sci. USA, 109(7):2473-8. PMCID: PMC3289296
  • Jeevan-Raj BP, Robert I, Heyer V, Page A, Wang JH, Cammas F, Alt FW, Losson R and Reina-San-Martin B (2011). Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination. Journal of Experimental Medicine, 208(8):1649-60. PMCID: PMC3149220
  • Boboila C, Jankovici M, Yan CT, Wang JH, Wesemann DR, Zhang T, Fazeli A, Feldmane L, Nussenzweig A, Nussenzweig M, Alt FW (2010).  Alternative End-joining Catalyzes Robust IgH Locus Deletions and Translocations in the Combined Absence of Ligase 4 and Ku70. Proc. Natl. Acad. Sci. USA, 107(7):3034-9.
  • Boboila C, Yan C, Wesemann DR, Jankovic M, Wang JH, Manis J, Nussenzweig A, Nussenzweig M, Alt FW (2010).  Alternative End-joining Catalyzes Class Switch Recombination in the Absence of Both Ku70 and DNA Ligase 4. Journal of Experimental Medicine, 207(2):417-27.
  • Ruccia F, Notarangeloa LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, Coakley K, Cheng HL, Feldman L, Wang JH, Balter B, Zha S, Detre C, Walter JE, Keszei M, Poliani PL, Giliani S, Terhorst C, Alt FW, Yan CT (2010).  Homozygous DNA Ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome. Proc. Natl. Acad. Sci. USA, 107(7):3024-9.
  • Wang JH, Gostissa M, Yan CT, Goff P, Hickernell T, Hansen E, Difilippantonio S, Wesemann DR, Zarrin AA, Rajewsky K, Nussenzweig A, Alt FW (2009). Mechanisms Promoting Translocations in Editing and Switching Peripheral B Cells. Nature, 460(7252), 231-6.  (News and Views published on Nature).
  • Wang JH, Alt FW, Gostissa M, Datta A, Murphy M, Alimzhanov MB, Coakley KM, Rajewsky K, Manis JP, Yan CT (2008).  Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. Journal of Experimental Medicine, 205(13), 3079-90.  (Commentary published on Cell).
  • Lee Y, Chin RK, Christiansen P, Sun Y, Tumanov AV, Wang J, Chervonsky A, and Fu Y-X (2006). Recruitment and Activation of Naive T Cells in the Islets by Lymphotoxin  Receptor-Dependent Tertiary Lymphoid Structure. Immunity, 25, 1-12.
  • Wang Y-G, Kim KD, Wang J, Yu P and Fu Y-X (2005).  Stimulating Lymphotoxin beta Receptor on the Dendritic Cells is Critical for Their Homeostasis and Expansion. Journal of Immunology, 175, 6997–7002.
  • Anders RA, Subudhi SK, Wang J, Pfeffer K, and Fu Y-X (2005). Contribution of the lymphotoxin beta receptor to liver regeneration. Journal of Immunology, 175, 1295–1300.
  • Wang J, Anders R A, Wang Y, Turner J R, Abraham C, Pfeffer K and Fu Y-X (2005).  The Critical Role of LIGHT in Promoting Intestinal Inflammation and Crohn’s Disease. Journal of Immunology, 174, 8173-8182.
  • Wang Y, Subudhi SK, Anders RA, Lo J, Sun Y, Blink S, Wang Y, Wang J, Liu X, Mink K, Degrandi D, Pfeffer K, and Fu Y-X (2005). The Role of Herpes Viral Entry Mediator as a Negative Regulator of T Cell-Mediated Responses. Journal of Clinical Investigation, 115, 711-717.
  • Zarrin AA, Tian M, Wang J, Borjeson T, and Alt FW (2005). Influence of Switch Region Length on Immunoglobulin Class Switch Recombination. Proc. Natl. Acad. Sci. USA, 102(7), 2466-2470.
  • Wang J, Anders R A, Wu Q, Peng D, Cho J H, Sun Y, Karaliukas R, Kang H S, Turner J R, Fu Y-X (2004). Dysregulated LIGHT expression on T Cells mediates intestinal inflammation and contributes to IgA nephropathy. Journal of Clinical Investigation, 113, 826-835. 
  • Yu P, Lee Y, Liu W, Chin R K, Wang J, Wang Y, Schietinger A, Schreiber H, and Fu Y-X (2004). Priming of naive T cells inside tumors leads to eradication of established tumors. Nature Immunology, 5, 141-149.  (News and Views published on Nature Immunology).
  • Wang J and Fu Y-X. LIGHT-mediated thymocyte selection is dependent on the interaction between TCR and MHC/peptide (2003). Journal of Immunology, 170, 3986-3993.
  • Wang J, Foster A, Chin R, Yu P, Wang Y, Pfeffer K and Fu Y-X (2002). The complementation of lymphotoxin deficiency with LIGHT, a newly discovered TNF family member, for the restoration of secondary lymphoid structure and function. European Journal of Immunology, 32, 1969-79.
  • Wang J, Lo J C, Foster A, Yu P, Chen H M, Wang Y, Tamada K, Chen L, and Fu Y-X (2001). The regulation of T cell homeostasis and autoimmunity by T cell derived LIGHT. Journal of Clinical Investigation, 108, 1771-1780.  (Commentary published on Journal of Clinical Investigation).
  • Wang J, Chun T, Lo J C, Wu Q, Wang Y, Foster A, Roca K, Chen M, Tamada T, Chen L, Wang C-R, and Fu Y-X (2001). The critical role of LIGHT, a TNF family member, in T cell development. Journal of Immunology 167, 5099-5105.
  • Wang Y, Wang J, Sun Y, Wu Q, Fu Y-X (2001). Complementary effects of TNF and lymphotoxin on the formation of germinal center and follicular dendritic cells.  Journal of Immunology, 166, 330-347.
  • Wu Q, Sun Y, Wang J, Lin X, Wang Y, Pegg L, Futterer A, Pfeffer K, and Fu Y-X (2001). Signal via lymphotoxin-beta R on bone marrow stromal cells is required for an early checkpoint of NK cell development. Journal of Immunology 166, 1684-1689. 
  • Wang Y, Huang G, Wang J, Molina H, Chaplin D.D, and Fu Y-X (2000). Antigen persistence is required for somatic mutation and affinity maturation of immunologloblin.  European Journal of Immunology, 30, 2226-2234.
  • Wu Q, Wang Y, Wang J, Hedgeman E.O, Browning J, and Fu Y-X (1999). The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues.  Journal of Experimental Medicine, 190, 629-38.

Reviews or Editorials:
  • Chen Z and Wang JH. Impact of Chromosomal Translocation and Genomic Instability on Personalized Medicine. Personalized Medicine, March 2013, Vol. 10, No. 2, Pages 111-114.
  • Wang JH (2013). The role of activation induced deaminase in antibody diversification and genomic instability. Immunologic Research, 2013 Mar;55(1-3):287-97. PMID: 22956489
  • Chaudhuri J, Basu U, Zarrin A, Yan C, Franco S, Perlot T, Vuong B, Wang J, Phan RT, Datta A, Manis J and Alt FW (2007).  Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism. Advances in Immunology, 94, 157-214.
  • Wang J and Fu Y-X (2005).  TNF family members and inflammatory bowel disease. Invited Review. Immunological Review 204, 144-155.
  • Chin R, Wang J and Fu Y-X. Lymphoid microenvironment in the gut for immunoglobulin A and inflammation (2003). Immunological Review, 195, 190-201.
  • Wang J and Fu Y-X (2004).  The role of LIGHT in T cell-mediated immunity. Immunologic Research, 30, 201-214.
  • Wang J and Fu Y-X (2004). The Role of LIGHT in Autoimmunity. Book Editor: Khare, Sanjay, Book Title: The TNF Superfamily (ISBN: 0-306-48231-2)

Click here for a list of Dr. Wang's recent publications.

Education

2002.9-2004.6

Ph.D. Pathology Program, University of Chicago, Chicago, IL.  Degree was granted in June, 2004.  Thesis Advisor: Dr. Yang-Xin Fu

1996.9-1998.12

Master of Science. Graduate Program in Department of Molecular Genetics, Ohio State University, Columbus, OH. Degree was granted in December, 1998.  Advisor: Dr. Berl Oakley

1991.8-1996.7 

Bachelor of Medicine (equivalent to M.D. in U.S.). Department of Basic Medical Sciences, Beijing Medical University, Beijing, P.R. China. Degree was granted in July, 1996.


Positions

2011.1-present 

Assistant Professor, Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health 

2009.6-2010.12 

Instructor of Pediatrics, Immune Disease Institute, Children’s Hospital Boston, Harvard Medical School. Lab PI: Dr. Frederick W. Alt.

2004.7-2009.6

Postdoctoral Research Fellow, Immune Disease Institute, Children’s Hospital Boston, Harvard Medical School. Lab PI: Dr. Frederick W. Alt.

1999.1-2002.8 

Research Associate, Department of Pathology, University of Chicago.  Lab PI: Dr. Yang-Xin Fu.


Honors/Awards

2014: AAI 2014Early Career Faculty Travel Award

2012: Outstanding Junior Faculty Award, National Jewish Health

2012-present: American Society of Hematology (ASH) Scholar Award

2011-2014: Boettcher Foundation Webb-Waring Early Career Investigator Award

2005-2008: Leukemia and Lymphoma Society (LLS) senior fellowship

1996-1997: Distinguished University Fellowship, Ohio State University

1996: GuangHua Scholarship, Beijing Medical University

Zhangguo Chen, Ph.D.
Assistant Research Professor
Zhangguo.Chen@ucdenver.edu

Xiaomi Chen, Ph.D.
Postdoctoral Fellow
Xiaomi.Chen@ucdenver.edu

Michael R. Rice
Student Research Assistant
Michael.Rice@ucdenver.edu

Postdoctoral fellow position available
Rotation inquiry welcomed