Mantle cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell non-Hodgkin's lymphoma (NHL) and still remains incurable with no standard of care for this disease Chemotherapy usually results in a tumor response but remissions are short. It carries the poorest prognosis among NHL subtypes with a median survival of 3 to 4 years (Lenz et al., 2004) due to the emergence of drug resistance. MCL still remains incurable and no standard of care exits for this disease. Therefore, new treatment strategies need to be developed and tested against human MCL. Mounting evidence now suggests that dynamic interactions between the lymphoma cell and its microenvironment in lymph nodes and bone marrow play a critical role in tumor development and response to therapy. Our recent publication has demonstrated that bone marrow stroma (BMS) protect lymphoma cells from chemotherapy-induced apoptosis by activating the non-canonical NF-:B (p52) pathway. Furthermore, our preliminary data has shown that BAFF (B cell activating factor belonging to the tumor necrosis factor [TNF] family) activates this pathway and plays a critical role in this protection. Depletion of BMS-produced BAFF abrogated stroma-mediated drug resistance. More recently we have shown that adhesion of MCL to BMS causes cell cycle arrest, which has been implicated in drug resistance. This study will extend our previous work by determining the relevance of BAFF and BAFF-induced p52 to BMS-mediated drug resistance and exploring the role of BAFF in cell cycle modulation. Our overall hypothesis is that stromal cell-derived BAFF uniquely provides a survival advantage to MCL cells to evade drug-induced death, and that targeting BAFF and BAFF-induced non-canonical NF-kB will result in enhanced cell death, and improve therapeutic response. We will evaluate the strategy of improving lymphoma cell response to cytotoxic agents by blocking BAFF-mediated cell survival pathways.
The specific aims for this project are as follows:
Aim 1. Determine the contribution of BAFF and BAFF-activated non-canonical NF-:B (p52) pathway in stroma- mediated drug resistance in MCL.
Aim 2. Determine the role of BAFF in stroma-mediated cell cycle arrest and examine the relationship between cell cycle arrest and drug resistance in MCL.
Aim 3. Target BAFF and its signaling pathways to sensitize MCL cells to drug-induced apoptosis in primary MCL samples. The proposed pre-clinical studies could potentially implement anti-BAFF based novel combination therapy and generate the rational to test their in vivo and in vitro efficacy against MCL.
Mounting evidence now suggests that dynamic interactions, between the cancer cells and its local and systemic microenvironment, play a critical role in tumor development and that all of the clinical properties of a tumor, including response to therapy, depend heavily on the tumor stroma. This study will contribute to understanding the influence of the microenvironment on lymphoma cell survival and drug resistance and identifying new molecular target for future therapies of lymphoma and other blood related tumors. The knowledge to be gained will allow us to improve therapy of lymphoma.
|Jiang, Huijuan; Lwin, Tint; Zhao, Xiaohong et al. (2018) Venetoclax as a single agent and in combination with PI3K-MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma. Br J Haematol :|
|Shain, K H; Dalton, W S; Tao, J (2015) The tumor microenvironment shapes hallmarks of mature B-cell malignancies. Oncogene 34:4673-82|
|Wang, Gang Greg; Konze, Kyle D; Tao, Jianguo (2015) Polycomb genes, miRNA, and their deregulation in B-cell malignancies. Blood 125:1217-25|
|Tao, Jiangchuan; Zhao, Xiaohong; Tao, Jianguo (2014) c-MYC-miRNA circuitry: a central regulator of aggressive B-cell malignancies. Cell Cycle 13:191-8|
|Lwin, Tint; Zhao, Xiaohong; Cheng, Fengdong et al. (2013) A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J Clin Invest 123:4612-26|
|Zhao, X; Lwin, T; Zhang, X et al. (2013) Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia 27:2341-50|
|Zhang, X; Chen, X; Lin, J et al. (2012) Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene 31:3002-3008|
|Zhang, Xinwei; Zhao, Xiaohong; Fiskus, Warren et al. (2012) Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 22:506-523|
|Lin, J; Lwin, T; Zhao, J-J et al. (2011) Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. Leukemia 25:145-52|
|Lwin, Tint; Lin, Jianhong; Choi, Yong Sung et al. (2010) Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA-181a. Blood 116:5228-36|