Y. Lynn Wang, MD, PhD, FCAP

Yue Lynn Wang, MD, PhD, FCAP
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Medical Director, Molecular Pathology

Professor, Department of Pathology; Blood Cell Development and Function

Specialties

Treatment Focus

CLL/Lymphoma and Molecular Pathology

Research Program

Lab Overview

As a physician-scientist, Dr. Wang is the principal investigator of several translational research projects on aberrant signal transduction pathways in B-cell lymphoma and leukemia.

1. Targeting B-cell receptor signaling (BCR) in lymphoid malignancies. Wang lab is one of the pioneers who explored the idea of targeting BCR signaling in lymphoid malignancies before BCR-directed therapies become 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.

  • 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 PMID: 18596745.
  • 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.
  • 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 PLC2 predict apoptotic response of chronic lymphocytic leukemia cells to SRC tyrosine kinase inhibitor dasatinib. Clin. Cancer Res. 16, 587-99, 2010.  PMID: 20068106.
  • 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. PMID: 22025527.
  • 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. PMID: 24270740.
  • Wu W, Wang W, Franzen CA, Guo H, Lee J, Li Y, Sukhanova M, Sheng D, Venkataraman G, Ming M, Lu P, Gao A, Xia C, Li J, Zhang LL, Jiang VC, Wang ML, Andrade J, and Wang YL. Inhibition of B-Cell Receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2. Blood Adv 5: 185–197, 2021

2. Mechanisms of resistance to BCR-targeted therapies. An important aspect of Dr. Wang’s work on BCR signaling-targeted therapies focuses on the characterization of the molecular mechanisms underlying drug sensitivity and resistance. In particular, Wang lab contributed significantly to the understanding of the mechanisms leading to primary and secondary resistance to BTK inhibition including their discovery of the BTK C481S mutation.

  • 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. N Engl J Med. 370: 2352-4. 2014. PMC4512173.
  • 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.  Leukemia. 29:895-900, 2015. Ranked as one of most highly cited papers published in Leukemia from 2015 in May 2019. PMID: 25189416.
  • 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. Br J Haematol. 166:849-61, 2014.  PMID: 24957109
  • Zhang SQ, Smith SM, Zhang SY, and Wang YL. Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and non-Hodgkin lymphoma. Br J Haematol. 170:445-56, 2015. PMID: 24957109
  • 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. PMID: 27626698. Oncotarget.7:68833-41, 2016
  • 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. PMC4826229.
  • Kadri S, Lee J, Fitzpatrick C, Galanina N, Sukhanova M, Venkataraman G, Sharma S, Long B, Petras K, Theissen M, … Lu P and Wang YL. Clonal Evolution underlying leukemia progression and Richter transformation in ibrutinib-relapsed CLL patients. Blood Advances 1:715-727, 2017. PMC5728051.

3. Strategies to overcome BCR resistance via blocking of other signaling pathways. Besides revealing the resistance mechanisms to BCR-targeted therapies, Wang Lab also works on developing strategies to overcome such resistance.

  • 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 36:3441-9, 2017. PMC5645670.
  • 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, 8:12953-12967, 2017. PMC5355069.
  • Ming M, Wu W, Xie B, Sukhanova M, Wang W, Kadri S, Sharma S, Lee J, Shacham S, Landesman Y, Maltsev N, Lu P, and Wang YL. XPO1 inhibition antagonizes MCL via nuclear retention of IkB: Selinexor demonstrates antitumor activities in both ibrutinib-sensitive and resistant tumor cells. Mol Cancer Ther. 17:2564-2574, 2018. PMID: 30510142
  • Lee J, Zhang LL, Wu W, Guo H, Li Y, Sukhanova M, Venkataraman G, Zhang H, Alikhan M, Lu P, Guo A, Galanina N, Andrade J, Wang ML and Wang YL.  Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma. Blood Adv. 2:2039-2051, 2018. PMC6113611.

4. Applications of new therapeutic models in lymphoma and CLL to the investigation of drug resistance. A new dimension of Wang Lab involves therapeutic models in lymphoma and CLL. They contributed to a collaborative project building lymphoma PDx models for personalized therapy. Their work on an ex vivo CLL proliferation model was orally presented at ASH 2019 and was recently published.

  • Zhang L, Nomie K, Zhang H, Bell T, Pham L, Kadri S, Segal J, Li S, Zhou S, Santos D, Richard S, Sharma S, Wang YL, and Wang M. B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy. Clin Can Res; 23:4212-4223, 2017. PMC5540787.
  • Lu P, Wang S, Franzen CA., Venkataraman G, McClure R, Li L, Wu W, Niu N, Sukhanova M, Pei J, Baldwin D, and Wang YL. Ibrutinib and venetoclax target distinct subpopulations of CLL cells: Implication for residual disease eradication. https://rdcu.be/cfsml. Blood Cancer Journal 11:39, 2021.

Dr. Y. Lynn Wang, a board-certified molecular pathologist, is specialized in the development and interpretation of molecular and genomic clinical assays including PCR, RT-PCR, FISH, Sanger sequencing and Next-gen sequencing assays. She served as the Founding Director of the Genomic and Molecular Pathology Division at the University of Chicago and Director of Molecular Hematopathology at Weill Cornell Medical College before she joined Fox Chase Cancer Center in 2018. She contributed >75 publications to the medical and scientific literature.  Many of them are well cited including the report in the New England Journal of Medicine and one of the top-cited articles in Leukemia.  Dr. Wang is an inventor on two issued US patents.

  • BTKC481S disrupts the covalent binding of ibrutinib to BTK
  • BTKC481S mutation restores the activity of the BCR signaling pathway
  • Novel ibrutinib-resistant BTKT316A mutation identified
  • Evolutionary dynamics of the major ibrutinib-resistant clones during disease relapse
  • Activation of MYC contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

     

    Twitter: @DrLynnWang

    Clinical Locations

    Educational Background

    • MD, University of the State of New York, NY, 2002
    • Postdoctoral Research, Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 2000-02
    • Residency, Clinical Pathology, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, 1998-2002
    • Fellowship, Molecular Pathology, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, 1995-97
    • PhD, Molecular Biology/Biochemistry, Department of Biochemistry, Brandeis University, Waltham, MA, 1995
    • MD, Beijing Medical University (AKA Peking University Health Science Center), China, 1988

    Certifications

    • Certified in Clinical Pathology, American Board of Pathology
    • Certified as a Laboratory Director in Genetic and Molecular Oncology Testing in the State of New York
    • Certified as a Laboratory Director in Molecular Oncology Testing in the State of New York
    • Certified in Molecular Genetic Pathology, American Board of Pathology/American College of Medical Genetics
    • Re-certified in Molecular Genetic Pathology, American Board of Pathology/American College of Medical Genetics

    Memberships

    • American Society for Investigative Pathology
    • American Society of Hematology
    • Association for Molecular Pathology
    • Elected Fellow, College of American Pathologists
    • United States and Canadian Academy of Pathology

    Honors & Awards

    • Yao Yuan Award for Research Excellence, 2017
    • Travel Award, American Society for Clinical Investigation, 2006, 2008 
    • Inventor on issued patent: Mutations associated with resistance to inhibitors of Bruton's tyrosine kinase (BTK). U.S. Patent No. 10,954,567.
    • Inventor on issued patent: BTK mutation and ibrutinib resistance. US20190153543

    People

    Research Interests

    ASH 2019: Distinct CLL cell populations provide rationale for combining drugs to minimize residual disease

    At the American Society of Hematology Meeting in December 2019, Dr. Y. Lynn Wang gave an overview of her team’s chronic lymphocytic leukaemia proliferation model, which has demonstrated the benefits of combining ibrutinib and venetoclax. Video from ASH 2019 (December 8, 2019. 5:11)

    Lab Overview

    Wang Lab works on signaling pathways and molecular-targeted therapies in CLL and non-Hodgkin lymphoma with emphasis on:

    • B-cell receptor signaling in non-Hodgkin lymphoma and CLL
    • Mechanisms of sensitivity and resistance to targeted therapies in non-Hodgkin lymphoma
    • Rational drug combinatin in non-Hodgkin lyphoma
    • Ex vivo models

    Misc

    • BTKC481S disrupts the covalent binding of ibrutinib to BTK
    • BTKC481S mutation restores the activity of the BCR signaling pathway
    • Novel ibrutinib-resistant BTKT316A mutation identified
    • Evolutionary dynamics of the major ibrutinib-resistant clones during disease relapse
    • Activation of MYC contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

      Selected Publications

      Nakhoda S, Vistarop A and Wang YL. Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2022 Aug 27. doi: 10.1111/bjh.18418. Online ahead of print

      Wu W., Wang W., Franzen C.A., Guo H., Lee J., Li Y., Sukhanova M., Sheng D., Venkataraman G., Ming M., Lu P., Gao A., Xia C., Li J., Zhang L.L., Jiang V.C., Wang M.L., Andrade J., Zhou X., Wang Y.L., Inhibition of b-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via rac2. Blood Adv. 5(1): 185-197, 2021. PMC7805322. https://www.ncbi.nlm.nih.gov/pubmed/33570628.

      Lu P, Wang S, Franzen CA., Venkataraman G, McClure R, Li L, Wu W, Niu N, Sukhanova M, Pei J, Baldwin D, Nejati RM, Wasik MA, Khan N, Tu Y, Gao J, Chen Y, Ma S, Larson RA and Wang YL. Ibrutinib and venetoclax target distinct subpopulations of CLL cells: Implication for residual disease eradication. Blood Cancer Journal 11:39, 2021 https://rdcu.be/cfsml.

      Lee J, Wang YL. Prognostic and Predictive Molecular Biomarkers in Chronic Lymphocytic Leukemia. The Journal of Molecular Diagnostics; 22(9):1114-1125. 2020. PubMed

      Lee J, Zhang LL, Wu W, Guo H, Li Y, Sukhanova M, Venkataraman G, Huang S, Zhang H, Alikhan M, Lu P, Guo A, Galanina N, Andrade J, Wang ML, Wang YL. Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma. Blood Adv; 2(16):2039-2051. 2018 PubMed

      Ming M, Wu W, Xie B, Sukhanova M, Wang W, Kadri S, Sharma S, Lee J, Shacham S, Landesman Y, Maltsev N, Lu P, Wang YL. XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB. Mol Cancer Ther; 17(12):2564-2574. 2018 PubMed

      Wang YL. MYD88 mutations and sensitivity to ibrutinib therapy. PMID:29482770. J Mol Diagn. 20:264-266, 2018 PubMed

      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, 8:12953-12967, 2017. PubMed

      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 36:3441-9, 2017 PubMed

      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 PubMed

      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. PMID: 26717038.  Oncotarget. 7: 4598-610, 2016 PubMed

      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. PMID: 27626698. Oncotarget.7:68833-41, 2016 PubMed

      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. Ranked as one of most highly cited papers published in Leukemia from 2015 in December 2017. PubMed

      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 PubMed

      Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, Raca G, Pandey A, Conley P, Yu H and Wang YL. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. PMID: 26575169. Oncotarget. 6: 43881-96, 2015. PubMed

      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. PMID:24270740. Leukemia, 28: 649-57, 2014. PubMed

      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. PubMed

      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. PubMed

      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. PubMed

      Additional Publications

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