Genomic and Molecular Pathology
Comprehensive Cancer Center
Committee on Cancer Biology
Lymphoma Translational Pathology
Department of Pathology
The University of Chicago
5841 S. Maryland Ave.
MC 1089, Room N-316A
Chicago, IL 60637
Y. Lynn Wang, MD, PhD, FCAP, is a professor and the Founding Medical Director of the Genomic and Molecular Pathology at the University of Chicago Medical Center. One of the major missions of the Division is to provide a comprehensive CLIA‐certified genetic and genomic laboratory service to enable personalized cancer treatment. This is accomplished by determining the genomic and genetic profile of each individual solid tumor or hematopoietic malignancy. The Division, founded in June 2013, was composed of four laboratories: the Molecular Diagnostics Laboratory, the Cytogenetics Laboratory, the Clinical Genomics Laboratory and the Translational Research Laboratory. Dr. Wang started by designing and building the Genomics Laboratory from a blueprint. In her three-year term as the Division Director, Dr. Wang, with assistance from other attendings, Drs. Jeremy Segal, Carrie Fitzpatrick, Larissa Furtado:
- Selected and equipped the laboratory with instruments for sample preparation, nucleic acid extraction, library preparation and high-throughput sequencing.
- Recruited a team of 29 people including medical technologists, PhD scientists, clinical associate, bioinformaticians and laboratory administrators.
- Developed and validated a total of 17 new molecular tests, including single-gene molecular/FISH tests and next-gen sequencing (NGS) assays. Among the single gene tests, quantitative BCR-ABL was validated against the International Scale. Amoung the NGS assays, OncoHeme, a 53-gene panel wen live in December 2014 and OncoPlus, a 1,212-gene panel, went in service in February 2016. As of May 2016, the total number of NGS test performed has exceeded 1,000. The annual test performed by the Division had increasted to ~3,750 altogether.
- Turned an existing problematic lab with multiple CAP quality deficiencies to a lab with zero deficiencies.
- Established a multi-disciplinary tumor board with Heme/Onc Section.
- Established contracts with pharmaceutical companies to conduct biomarker studies on samples collected from multi-center clinical trials.
- Published 10 Papers in NEJM, Leukemia, JAMA Oncology, BJH, Oncotarget and other peer-reviewed journals.
For more information on some of the CLIA-certified tests:
Translational Research Interests
As a physician-scientist and the Director of Lymphoma Translational Pathology, Dr. Wang is the principal investigator of several translational research projects on aberrant signal transduction pathways in B-cell lymphoma and leukemia. The Wang lab is one of the pioneers who explored the idea of targeting BCR signaling in lymphoid malignancies before BCR-directed therapies became well-known and successful. Using inhibitors of LYN, SYK and BTK, the lab has demonstrated the critical role of BCR signaling in lymphoma cell proliferation and survival in diffuse large B cell lymphoma (DLBCL), CLL and mantle cell lymphoma. Their work on dasatinib response prediction in DLBCL has led to the successful development of a Phase II clinical trial at Weill Cornell where she worked.
Dr. Wang’s work on B-cell receptor signaling and BCR-targeted therapies has extended to the characterization of the molecular mechanisms underlying drug sensitivity and resistance. In particular, the Wang lab contributed significantly to the understanding of the mechanisms leading to primary and secondary resistance to SYK and BTK inhibition. In May 2014, the lab reported their discovery of BTKC481S mutation in a CLL patient with ibrutinib (a BTK inhibitor) resistance in the NEJM. [UC News Release on Dr. Wang's work on ibrutinib resistance in CLL] That was followed by several studies elucidating the molecular mechanisms of primary and secondary resistance to ibrutinib in CLL and MCL.
Projects in Wang Lab involve a variety of molecular, cellular, immunological, biochemical, pharmacological and genomic techniques, providing a good opportunity for learning. Many of these projects engage collaborations with other scientists, pathologists and heme/onc physicians at home and outside institutions, as well as with industrial partners. Dr. Wang is a well accomplished investigator who has authored or co-authored 63 original scientific publications. She has given >70 invited extramural oral presentations.
Extramurally, Dr. Wang was a member of the International BCR-ABL RQ-PCR Standardization Group, whose 5-year work has led to the establishment of the first WHO International Genetic Reference Panel for quantification of BCR-ABL in CML monitoring.
In addition, Dr. Wang was an elected officer of the Association for Molecular Pathology (AMP). She was a member of the Expert Panel of the Molecular Oncology Reference Materials program of the Center for Disease Control and Prevention. She was part of the AMP JAK2/MPL mutation Guideline Working Group whose work led to the publication of laboratory practice guidelines. Besides AMP, Dr. Wang is a member of the College of American Pathologists, US and Canadian Academy of Pathology, American Society for Investigative Pathology and American Society of Hematology. She reviews manuscripts for many professional journals including Blood, Leukemia, Cancer Cell and Science Translational Medicine.
Training and Past Experience
Dr. Wang received her MD from Beijing Medical University in 1988 (conferred to a US MD degree in 2002) and her PhD from Brandeis University in 1996. She completed her Clinical Pathology Residency, Clinical Molecular Pathology Fellowship and postdoctoral research training at the University of Pennsylvania. She is board-certified in Clinical Pathology and Molecular Genetic Pathology. Before joining the faculty of the University of Chicago, she directed the Molecular Hematopathology Laboratory and her lymphoma translational research laboratory at Weill Cornell Medical College for 11 years from 2002-2013.
Selected Peer-Reviewed Publications
B-cell receptor signaling and lymphomagenesis
1. Yang C, Lu P, Lee FY, Chadburn A, Barrientos JC, Leonard JP, Ye F, Zhang D, Knowles DM, and Wang YL. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: Molecular basis for anti-tumor activity and drug resistance of dasatinib. Leukemia. 22, 1755-66, 2008
2. Lu P, Yang C, Guasparri I, Harrington W, Wang YL*, and Cesarman E*. Early events of B-cell receptor signalling are not essential for the proliferation and viability of AIDS-related lymphoma. Leukemia. 23, 807-10, 2009. *Co-corresponding author.
3. Song Z, Lu P, Furman RR, Leonard JP, Martin P, Tyrell L, Lee FY, Knowles DM, Coleman M, and Wang YL. Activity of SYK and PLCg2 predict apoptotic response of chronic lymphocytic leukemia cells to SRC tyrosine kinase inhibitor dasatinib. Clin. Cancer Res. 16, 587-99, 2010.
4. Nie K, Zhang T, Allawi H, Gomez M, Liu Y, Chadburn A, Wang YL, Knowles DM, and Tam W. Down-Regulation of PRDM1/Blimp-1 in diffuse large B-cell lymphomas: A potential role of microRNA let-7. Am. J. Pathol. 177, 1470-9, 2010.
5. Chadburn A, Wilson J, and Wang YL. Molecular and Immunohistochemical Detection of Kaposi Sarcoma Herpesvirus / Human Herpesvirus-8. Methods Mol Biol. 999:245-56, 2013
6. Nayar U, Lu P, Goldstein RL, Vider J, Ballon G, Rodina A, Taldone T, Erdjument-Bromage H, Blasberg R, Melnick A, Cerchietti L, Chiosis G, Wang YL*, Cesarman E*. Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 122:2837-47. 2013 *Co-corresponding authors.
7. Wang YL, Cesarman E, and Knowles DM. Antigen Receptor Genes: Structure, Function, and Molecular Analysis in Clinical Applications. Knowles’ Neoplastic Hematopathology. 3rd Ed, 156-167, 2013
8. Guo A, Lu P, Lee J, Zhen CJ, Chiosis G, Wang YL. HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene. 2017 Jan 23. doi: 10.1038/onc.2016.494. [Epub ahead of print]
Sensitivity and resistance to B-cell receptor targeted therapies
1. Cheng S, Coffey G, Zhang XH, Shaknovich R, Song Z, Lu P, Pandey A, Melnick AM, Sinha U and Wang YL. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood. 118, 6342-52, 2011
2. Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M, Liu M, Buggy JJ, Furman RR, and Wang YL. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia, 28: 649-57, 2014.
3. Furman RR*, Cheng S*, Lu P*, Setty M, Perez A, Guo A, Racchumi J, Xu G, Ma J, Coleman M, Buggy J, Leslie C, and Wang YL. Ibrutinib resistance in chronic lymphocytic leukemia. PMID:24869597. N Engl J Med. 370: 2352-4. 2014 *Co-first authors
4. Ma J, Lu P, Guo A, Cheng S, Zong H, Martin P, Coleman M, and Wang YL. Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells. PMID:24957109. Br J Haematol. 166:849-61, 2014.
5. Cheng S, Guo A, Lu P, Ma J, Coleman M, and Wang YL. Functional Characterization of BTKC481S mutation that confers ibrutinib resistance: Exploration of alternative kinase inhibitors. PMID: 25189416. Leukemia. 29:895-900, 2015.
6. Zhang SQ, Smith SM, Zhang SY, and Wang YL. Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and non-Hodgkin lymphoma. PMID:25858358. Br J Haematol. 170:445-56, 2015
7. Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, Raca G, Pandey A, Conley P, Yu H and Wang YL. Dual SYK/JAK inhibition has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. PMID: 26575169. Oncotarget. 6: 43881-96, 2015
8. Guo A, Lu P, Galanina N, Nabhan C, Smith SM, Coleman M, and Wang YL. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib. Oncotarget. 7: 4598-610, 2016
9. Sharma S, Galanina N, Guo A, Lee J, Kadri S, Van Slambrouck C, Long B, Ming M, Furtado LV, Segal, JP, Stock W, Venkataraman G, Tang W-J, Lu P, and Wang YL. Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL. Oncotarget.7:68833-41,2016
10. Guo A, Lu P, Coffey G, Conley P, Pandey A, and Wang YL. Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment Ongotarget, published online January 10, 2017. DOI: 10.18632/oncotarget.14588.
11. Kadri S, Lee J, Fitzpatrick C, Galanina N, Sukhanova M, Venkataraman G, Sharma S, Long B, Petras K, Theissen M, Ming M, Kobzev Y, Kang W, Guo A, Wang W, Niu N, Weiner H, Thirman M, Stock W, Smith SM, Nabhan, C, Segal JP, Lu P and Wang YL. Clonal Evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL. Blood Advances 1:715-727, 2017. http://www.bloodadvances.org/content/1/12/715
12/2013 Interviewed and featured in OncUView® TV on “Dual SYK/JAK Inhibition Has a Broader Anti-Tumor Activity in Both ABC and GCB Types of Diffuse Large B Cell Lymphoma” (accessible through YouTube by searching “Lynn Wang”) https://www.youtube.com/watch?feature=player_detailpage&v=WH2GpSnazQc
05/14 NCI Cancer Center News: Tiny mutation triggers drug resistance for patients with one type of leukemia (PDF link)
05/14 University of Chicago News Release http://www.uchospitals.edu/news/2014/20140528-leukemia.html
05/14 Science Life
05/14 Hematology Times. Mutation causes ibrutinib resistance in CLL. http://www.hematologytimes.com/p_article.do?id=4188
05/14 Kids Cures Foundation http://kidscures.org/tiny-mutation-triggers-drug-resistance-for-patients-with-one-type-of-leukemia/
Fall 2015 Galanina N, Wang YL and Smith SM. New challenges and personalized therapies in CLL. Frontline, Lymphoma Research Foundation Newsletter, Fall 2015 issue.
12/2015 Interviewed and featured in Oncology.TV on “EvaluatingCerdulatinib in Diffuse large B Cell Lymphoma” http://oncology.tv/OncologyTVNetwork/TabId/1455/VideoId/1541/Dr-Lynn-Wang-Discusses-Evaluating-Cerdulatinib-In-Diffuse-Large-B-Cell-Lymphoma.aspx