Jianguo Tao, M.D., Ph.D.

Professor of Pathology

EDUCATION:

Medical School: Peking Medical University,  1990
Residency: Long Island Jewish Medical Center
Fellowship: University of Pennsylvania Medical Center (Hematopathology)

CLINICAL:

Pathology; Hematopathology

RESEARCH: 

I am a trained clinical hematopathologist and physician-scientist who is well versed in both basic and translational studies in hematologic tumors, with a special interest and emphasis in B-cell malignancies: the genetic and epigenetic mechanisms of tumor microenvironment (TME)-induced survival and drug resistance. My long-term goal is to characterize the pathobiology of B-cell lymphomas, especially aggressive B-cell malignancies, and the evolution of resistance to drugs and, more recently, immunotherapy. We discovered that, in addition to , super enhancer remodeling and transcriptome activation upon either ibrutinib or venetoclax treatment drive kinome reprogramming and subsequent therapy resistance emergence. Thus, targeting transcription machinery activation state as a whole, such as with CDK9 inhibition, is a novel strategy to delay and overcome drug resistance evolution. Recently, we extend our investigations to the identification of major molecular determinants for responses and resistance to CDK9 inhibitors and CAR-T therapy, and novel targets for overcoming or preventing therapy resistance evolution in aggressive B-cell lymphomas such as mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). We seek to apply our expertise in TME-mediated resistance, acquired drug resistance, and genomic and non-genomic regulation to immunotherapy, such as CAR-T therapy, in both MCL and DLBCL. This led us to identify a novel immunosuppressive determinant in TME stromal cells that imposes a significant obstacle to the efficacy of CAR-T therapy in diffuse large B-cell lymphoma and MCL. We additionally identified and transcription machinery activation as a novel vulnerability for therapy resistance evolution. Over the last decade, I have developed an active and unique research program for drug screening, chemical proteomics profiling, bulk and scRNAseq, ChIP-seq, ATAC, scATAC, functional pharmacogenomic computational biology, and multiplex immune profiling, and applied it to cell line and primary lymphoma samples to determine the major intrinsic and TME extrinsic molecular determinants governing lymphoma cell response and resistance.  By capitalizing a “” opportunity and approach, my long-term goal is to provide major advances in our understanding of the lymphoma biology, develop innovative therapies and exert an immediate favorable impact on treatment for lymphoma patients.  My extensive background in cancer biology and clinical hematology/oncology, with my expertise in novel lymphoma therapies and therapy resistance, make me well-suited to serve as a Principal Investigator on many projects.

Contributions to Science

1. Tumor microenvironment, drug resistance, and B-cell malignancies: For the last decade, my laboratory has independently studied the role of stroma-mediated B-cell lymphoma survival, drug resistance, and tumor progression. We have demonstrated that the lymphoma TME is a critical determinant for lymphoma initiation, progression, response to therapy, and drug resistance. Specific niches of the TME provide a sanctuary for subpopulations of lymphoma cells to evade or circumvent drug-induced cell death, representing a form of de novo drug resistance. Furthermore, the subpopulation of cells surviving initial treatment develop deregulated genetic and epigenetic mechanisms, resulting in disease progression.  Blocking genetic alterations such as NF-κB pathway and epigenetic alterations such as miR-181a and HDAC can overcome stroma-mediated drug resistance and . My lab is at the forefront of identifying important cellular, signaling and epigenetic mechanisms involved in stroma-induced lymphoma survival and drug resistance.
2. Mantle cell lymphoma, transcription activation, and epigenetic regulation: MCL is an aggressive B-cell lymphoma that accounts for ~6-8% of all B-cell lymphomas; it typically has poor clinical outcomes due to the emergence of drug resistance. In 2004 we created and I became co-leader of the MCL Multidisciplinary Team at Moffitt Cancer Center and currently are assembling a strong MCL translation team at UVA. I was the cornerstone and instrumental for this team, from initial acquisition of MCL cell lines and distribution of MCL patient samples through project integration.  My lab was the first to demonstrate that miRNAs (miR-29) are associated with MCL prognosis and drive oncogenic pathways (such as CDK6, IGF-R) in MCL. We further studied the underlying mechanism of miRNA dysregulation by exploring the role of epigenetic (HDAC3, EZH2) and transcriptional (c-Myc) miRNA gene expression in MCL and other B-cell lymphomas. We found that many tumor suppressor miRNAs, such as miR-29, miR-26, and miR15a/16, are down-regulated in aggressive lymphomas, including MCL, and inversely correlated with c-Myc overexpression. Indeed, our work has led to the seminal discovery of epigenetic regulation of miRNA in B-cell lymphomas that involves histone deacetylase 3 (HDAC3) and EZH2, a novel mechanism and target for cMyc-driven lymphomagenesis. Recently, we further demonstrated that the rewired signaling programs and marked changes in the transcriptome drive aggressive progression of lymphoma and drug resistance evolution. We implemented chromatin immunoprecipitation sequencing (ChIP-seq) specific for acetylated lysine-27 of histone H3 (H3K27ac) and discovered that transcriptome reprogramming was attributed to super enhancer remodeling in MCL and DLBCL. This study uncovered the novel molecular mechanism for Myc-induced oncogenesis by suppressing the gene expression tumor suppressor.
3.  Transcription machinery activation as a novel vulnerability for therapy resistance evolution. Recently, B-cell receptor (BCR) inhibitors have been shown to be promising single therapeutic agents for B-cell lymphomas. The initial success of these agents is likely attributed to attenuation of BCR-dependent lymphoma-TME interactions. However, data is limited on BCR inhibitors in aggressive lymphomas, including diffuse large B-cell lymphomas (DLBCL) and MCL, though it appears that when used as single agents they produce a good but not durable response. These patients eventually developed ibrutinib resistance (acquired drug resistance) leading to fatal progression of MCL and DLBCL. We investigated the role of BCR signaling in stroma-mediated cell survival and associated acquired drug resistance in MCL and DLBCL. We demonstrated that stroma induced kinome reprogramming that resulted in multiple kinase signaling activation and governed tumor cell intrinsic as well as stroma-mediated extrinsic survival signals. In this process, the PI3K-AKT-mTOR axis functions as a central unifying hub to facilitate TME-lymphoma interaction and promote the development of acquired drug resistance. Next, we revealed that, in addition to drug pressure selection, super enhancer remodeling and transcriptome activation following ibrutinib or venetoclax treatment drive kinome reprogramming and subsequent therapy resistance emergence.  Thus, targeting transcription machinery activation, as a whole, is novel strategy to delay and overcome drug resistance evolution.

REFERENCES:

Jiang H, Lwin T, Zhao X, Yuan R, Grace L, Moscinski L, Shah B, Tao J. Venetoclax as a single agent and in combination with PI3K-MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mangle cell lymphoma (MCL). Br J Haematol. 2019 Jan; 84(2):298-302.

Zhao X, Wang M, Lwin T, Shain K, Wang M, Sotomayor E, Shah B, Tao, J. Transcriptional programming drives ibrutinib-resistance evolution in mantle cell lymphoma. Cell Reports. 2021 Mar 16; 34(11):108870

Wang MY, Li T, Ren Y, Shah BD, Lwin T, Gao J, Shain KH, Zhang W, Zhao X, Tao J. MCL-1 dependency as a novel vulnerability for aggressive B-cell lymphomas. Blood Cancer J. 2021 Jan 14;11(1):14.

Gao J, Wang M, Shah, B, Ren Y, Lwin T, Sotomayor E, Shain K, Zhao X, Tao J. CDK12 inhibition response and resistance in aggressive B-cell lymphomas.  Haematologica. 2021 Jun 24. doi:10.3324/haematol.2021.278743

Zhao X, Ren Y, Lawlor M, Shah BD, Park PM, Lwin T, Wang X, Liu K, Wang M, Gao J, Li T, Xu M, Silva A, Lee K, Zhang T, Koomen JM, Jiang H, Sudalagunta PR, Meads MB, Cheng F, Bi C, Fu K, Fan H, Dalton WS, Moscinski LC, Shain KH, Sotomayor EM, Wang G, Gray NS, Cleveland JL, Qi J, and Tao J. BCL2 amplicon loss and transcriptional remodeling can drive ABT-199 resistance in B-cell lymphoma models.  Cancer Cell, 2019 May 13;35(5):752-766.

Ren Y, Bi C, Zhao X, Lwin T, Wang C, Yuan J, Silva AS, Shah BD, Fang B, Li T, Koomen JM, Jiang H, Chavez JC, Pham LV, Sudalagunta PR, Wan L, Wang X, Dalton WS, Moscinski LC, Shain KH, Vose J, Cleveland JL, Sotomayor EM, Fu K, Tao J. PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. J Clin Invest. 2018, 3: 128(12):5517-5530.

Zhao X , Lwin T, Silva A, Shah B, Tao J,  Fang B, Zhang L, Fu K, Li J,  Jiang H, Meads MB, Jacobson T, Silva M, Distler A, Darville L, Zhang L, Han Y, Rebatchouk D, Di Liberto M, Moscinski LC, Koomen JM, Dalton WS, Shain KH, Wang M, Sotomayor E, and Tao J.

Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma.  Nature Commun. 2017 Apr 18;8:14920

Lwin T, Zhao X, Cheng F, Zhang X, Huang A, Shah B, Zhang Y, Moscinski LC, Choi YS, Kozikowski    AP, Bradner JE, Dalton WS, Sotomayor E, Tao J. A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J Clin Invest. 2013 Nov 1;123(11):4612-26.

Zhao X, Lwin T, Zhang X, Huang A, Wang J, Marquez V, Cheng-Kiang S, Dalton WS, Wright K, Sotomayor EM, Bhalla K, Tao J. Disruption of MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia. 2013.  Dec;27(12):2341-50. PMID 23538750

Wang GG, Konze KD, and Tao J.  Polycomb genes, miRNA, and their deregulation in B-cell malignancies.  Blood.  2015 2015 Feb 19; 125(8):1217-25

Zhang. X., Zhao, X., Fiskus, W., Lin, J., Lwin, T., Rao, R., Chan, JC., Fu. K., Marquez, V., Cheng-Kiang, S., Moscinski, L., Seto, E., Dalton, WS., Wright, K., Sotomayor, EM., Bhalla, K. and Tao, J. c-Myc-mediated miR-29 repression through coordinated epigenetic silencing of HDAC3 and polycomb-repressive complex 2 (PRC2) is a novel therapeutic target of histone modifications in aggressive B-cell lymphomas. Cancer Cell. 2012 Oct 16;22(4):506-23. PMID 23079660.