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5. PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas

Author

Ren, Yuan, Bi, Chengfeng, Zhao, Xiaohong, Lwin, Tint, Wang, Cheng, Yuan, Ji, Silva, Ariosto S., Shah, Bijal D., Fang, Bin, Li, Tao, Koomen, John M., Jiang, Huijuan, Chavez, Julio C., Pham, Lan V., Sudalagunta, Praneeth R., Wan, Lixin, Wang, Xuefeng, Dalton, William S., Moscinski, Lynn C., Shain, Kenneth H., Vose, Julie, Cleveland, John L., Sotomayor, Eduardo M., Fu, Kai, and Tao, Jianguo

Subjects
Gene expression -- Research, Lymphocytic leukemia -- Care and treatment -- Genetic aspects -- Patient outcomes, Health care industry
Abstract

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression, and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability, and in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the antiapoptotic protein MCL-1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival, and tumorigenicity, supporting clinical targeting of PLK1 in DHL., Introduction MYC is a transcription factor that promotes oncogenesis by activating and repressing target genes that control cell growth, metabolism, and division (1, 2). MYC is deregulated in a large [...]

Published
2018
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6. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

Author

Deng, Manman, Zhang, Mingzhi, Xu-Monette, Zijun Y., Pham, Lan V., Tzankov, Alexandar, Visco, Carlo, Fang, Xiaosheng, Bhagat, Govind, Zhu, Feng, Dybkaer, Karen, Chiu, April, Tam, Wayne, Zu, Youli, Hsi, Eric D., Choi, William W. L., Huh, Jooryung, Ponzoni, Maurilio, Ferreri, Andrés J. M., Møller, Michael B., Parsons, Benjamin M., van Krieken, J. Han, Piris, Miguel A., Winter, Jane N., Hagemeister, Fredrick, Alinari, Lapo, Li, Yong, Andreeff, Michael, Xu, Bing, and Young, Ken H.

Published
2020
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7. Supplementary Tables from Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL

Author

Xu-Monette, Ziju Y., primary, Xiao, Min, primary, Au, Qingyan, primary, Padmanabhan, Raghav, primary, Xu, Bing, primary, Hoe, Nicholas, primary, Rodríguez-Perales, Sandra, primary, Torres-Ruiz, Raul, primary, Manyam, Ganiraju C., primary, Visco, Carlo, primary, Miao, Yi, primary, Tan, Xiaohong, primary, Zhang, Hongwei, primary, Tzankov, Alexandar, primary, Wang, Jing, primary, Dybkær, Karen, primary, Tam, Wayne, primary, You, Hua, primary, Bhagat, Govind, primary, Hsi, Eric D., primary, Ponzoni, Maurilio, primary, Ferreri, Andrés J.M., primary, Møller, Michael B., primary, Piris, Miguel A., primary, van Krieken, J. Han, primary, Winter, Jane N., primary, Westin, Jason R., primary, Pham, Lan V., primary, Medeiros, L. Jeffrey, primary, Rassidakis, George Z., primary, Li, Yong, primary, Freeman, Gordon J., primary, and Young, Ken H., primary

Published
2023
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8. Supplementary Table 1 from In Vitro and In Vivo Therapeutic Efficacy of Carfilzomib in Mantle Cell Lymphoma: Targeting the Immunoproteasome

Author

Zhang, Liang, primary, Pham, Lan V., primary, Newberry, Kate J., primary, Ou, Zhishuo, primary, Liang, Rong, primary, Qian, Jianfei, primary, Sun, Luhong, primary, Blonska, Marzenna, primary, You, Yun, primary, Yang, Jing, primary, Lin, Xin, primary, Rollo, Alex, primary, Tamayo, Archito T., primary, Lee, John, primary, Ford, Richard J., primary, Zhao, Xiurong, primary, Kwak, Larry W., primary, Yi, Qing, primary, and Wang, Michael, primary

Published
2023
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9. Data from Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents

Author

Deng, Manman, primary, Xu-Monette, Zijun Y., primary, Pham, Lan V., primary, Wang, Xudong, primary, Tzankov, Alexandar, primary, Fang, Xiaosheng, primary, Zhu, Feng, primary, Visco, Carlo, primary, Bhagat, Govind, primary, Dybkaer, Karen, primary, Chiu, April, primary, Tam, Wayne, primary, Zu, Youli, primary, Hsi, Eric D., primary, You, Hua, primary, Huh, Jooryung, primary, Ponzoni, Maurilio, primary, Ferreri, Andrés J.M., primary, Møller, Michael B., primary, Parsons, Benjamin M., primary, Hagemeister, Fredrick, primary, van Krieken, J. Han, primary, Piris, Miguel A., primary, Winter, Jane N., primary, Li, Yong, primary, Xu, Bing, primary, Liu, Phillip, primary, and Young, Ken H., primary

Published
2023
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10. Data from Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL

Author

Xu-Monette, Ziju Y., primary, Xiao, Min, primary, Au, Qingyan, primary, Padmanabhan, Raghav, primary, Xu, Bing, primary, Hoe, Nicholas, primary, Rodríguez-Perales, Sandra, primary, Torres-Ruiz, Raul, primary, Manyam, Ganiraju C., primary, Visco, Carlo, primary, Miao, Yi, primary, Tan, Xiaohong, primary, Zhang, Hongwei, primary, Tzankov, Alexandar, primary, Wang, Jing, primary, Dybkær, Karen, primary, Tam, Wayne, primary, You, Hua, primary, Bhagat, Govind, primary, Hsi, Eric D., primary, Ponzoni, Maurilio, primary, Ferreri, Andrés J.M., primary, Møller, Michael B., primary, Piris, Miguel A., primary, van Krieken, J. Han, primary, Winter, Jane N., primary, Westin, Jason R., primary, Pham, Lan V., primary, Medeiros, L. Jeffrey, primary, Rassidakis, George Z., primary, Li, Yong, primary, Freeman, Gordon J., primary, and Young, Ken H., primary

Published
2023
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11. Supplementary Figure 1 from In Vitro and In Vivo Therapeutic Efficacy of Carfilzomib in Mantle Cell Lymphoma: Targeting the Immunoproteasome

Author

Zhang, Liang, primary, Pham, Lan V., primary, Newberry, Kate J., primary, Ou, Zhishuo, primary, Liang, Rong, primary, Qian, Jianfei, primary, Sun, Luhong, primary, Blonska, Marzenna, primary, You, Yun, primary, Yang, Jing, primary, Lin, Xin, primary, Rollo, Alex, primary, Tamayo, Archito T., primary, Lee, John, primary, Ford, Richard J., primary, Zhao, Xiurong, primary, Kwak, Larry W., primary, Yi, Qing, primary, and Wang, Michael, primary

Published
2023
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12. Supplementary Tables 1-5 and Supplementary Figures 1-8 from Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents

Author

Deng, Manman, primary, Xu-Monette, Zijun Y., primary, Pham, Lan V., primary, Wang, Xudong, primary, Tzankov, Alexandar, primary, Fang, Xiaosheng, primary, Zhu, Feng, primary, Visco, Carlo, primary, Bhagat, Govind, primary, Dybkaer, Karen, primary, Chiu, April, primary, Tam, Wayne, primary, Zu, Youli, primary, Hsi, Eric D., primary, You, Hua, primary, Huh, Jooryung, primary, Ponzoni, Maurilio, primary, Ferreri, Andrés J.M., primary, Møller, Michael B., primary, Parsons, Benjamin M., primary, Hagemeister, Fredrick, primary, van Krieken, J. Han, primary, Piris, Miguel A., primary, Winter, Jane N., primary, Li, Yong, primary, Xu, Bing, primary, Liu, Phillip, primary, and Young, Ken H., primary

Published
2023
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13. Supplementary Figures 1-3 from Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL

Author

Xu-Monette, Ziju Y., primary, Xiao, Min, primary, Au, Qingyan, primary, Padmanabhan, Raghav, primary, Xu, Bing, primary, Hoe, Nicholas, primary, Rodríguez-Perales, Sandra, primary, Torres-Ruiz, Raul, primary, Manyam, Ganiraju C., primary, Visco, Carlo, primary, Miao, Yi, primary, Tan, Xiaohong, primary, Zhang, Hongwei, primary, Tzankov, Alexandar, primary, Wang, Jing, primary, Dybkær, Karen, primary, Tam, Wayne, primary, You, Hua, primary, Bhagat, Govind, primary, Hsi, Eric D., primary, Ponzoni, Maurilio, primary, Ferreri, Andrés J.M., primary, Møller, Michael B., primary, Piris, Miguel A., primary, van Krieken, J. Han, primary, Winter, Jane N., primary, Westin, Jason R., primary, Pham, Lan V., primary, Medeiros, L. Jeffrey, primary, Rassidakis, George Z., primary, Li, Yong, primary, Freeman, Gordon J., primary, and Young, Ken H., primary

Published
2023
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14. Data from In Vitro and In Vivo Therapeutic Efficacy of Carfilzomib in Mantle Cell Lymphoma: Targeting the Immunoproteasome

Author

Zhang, Liang, primary, Pham, Lan V., primary, Newberry, Kate J., primary, Ou, Zhishuo, primary, Liang, Rong, primary, Qian, Jianfei, primary, Sun, Luhong, primary, Blonska, Marzenna, primary, You, Yun, primary, Yang, Jing, primary, Lin, Xin, primary, Rollo, Alex, primary, Tamayo, Archito T., primary, Lee, John, primary, Ford, Richard J., primary, Zhao, Xiurong, primary, Kwak, Larry W., primary, Yi, Qing, primary, and Wang, Michael, primary

Published
2023
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16. Table S1 from Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Author

Pham, Lan V., primary, Huang, Shengjian, primary, Zhang, Hui, primary, Zhang, Jun, primary, Bell, Taylor, primary, Zhou, Shouhao, primary, Pogue, Elizabeth, primary, Ding, Zhiyong, primary, Lam, Laura, primary, Westin, Jason, primary, Davis, R. Eric, primary, Young, Ken H., primary, Medeiros, L. Jeffrey, primary, Ford, Richard J., primary, Nomie, Krystle, primary, Zhang, Leo, primary, and Wang, Michael, primary

Published
2023
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18. Figure S2 from Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Author

Pham, Lan V., primary, Huang, Shengjian, primary, Zhang, Hui, primary, Zhang, Jun, primary, Bell, Taylor, primary, Zhou, Shouhao, primary, Pogue, Elizabeth, primary, Ding, Zhiyong, primary, Lam, Laura, primary, Westin, Jason, primary, Davis, R. Eric, primary, Young, Ken H., primary, Medeiros, L. Jeffrey, primary, Ford, Richard J., primary, Nomie, Krystle, primary, Zhang, Leo, primary, and Wang, Michael, primary

Published
2023
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19. Supplementary Figure Legends from Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Author

Pham, Lan V., primary, Huang, Shengjian, primary, Zhang, Hui, primary, Zhang, Jun, primary, Bell, Taylor, primary, Zhou, Shouhao, primary, Pogue, Elizabeth, primary, Ding, Zhiyong, primary, Lam, Laura, primary, Westin, Jason, primary, Davis, R. Eric, primary, Young, Ken H., primary, Medeiros, L. Jeffrey, primary, Ford, Richard J., primary, Nomie, Krystle, primary, Zhang, Leo, primary, and Wang, Michael, primary

Published
2023
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20. Targetable vulnerability of deregulated FOXM1/PLK1 signaling axis in diffuse large B cell lymphoma

Author

Yu, Fang, He, Hua, Nastoupil, Loretta J, Xu-Monette, Zijun Y, Pham, Ky, Liang, Yong, Chen, Guang, Fowler, Nathan H, Yin, C Cameron, Tan, Dongfeng, Yang, Yaling, Hu, Shimin, Young, Ken H, Pham, Lan V, and You, M James

Subjects
Original Article
Abstract

FOXM1 is a transcription factor that controls cell cycle regulation, cell proliferation, and differentiation. Overexpression of FOXM1 has been implicated in various cancer types. However, the activation status and functional significance of FOXM1 in diffuse large B cell lymphoma (DLBCL) have not been well investigated. Using proteomic approaches, we discovered that the protein expression levels of FOXM1 and PLK1 were positively correlated in DLBCL cell lines and primary DLBCL. Expression levels of FOXM1 and PLK1 mRNAs were also significantly higher in DLBCL than in normal human B cells and could predict poor prognosis of DLBCL, particularly in patients with germinal center B cell-like (GCB) DLBCL. Furthermore, proteomic studies defined a FOXM1-PLK1 signature that consisted of proteins upstream and downstream of that axis involved in the p38-MAPK-AKT pathway, cell cycle, and DNA damage/repair. Further studies demonstrated a mechanistic function of the FOXM1/PLK1 axis in connection with the DNA damage response pathways regulating the S/G2 checkpoint of the cell cycle. Therapeutic targeting of FOXM1/PLK1 using a FOXM1 or PLK1 inhibitor, as well as other clinically relevant small-molecule inhibitors targeting ATR-CHK1, was highly effective in DLBCL in vitro models. These findings are instrumental for lymphoma drug discovery aiming at the FOXM1/PLK1/ATR/CHK1 axis.

Published
2022

26. Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase–dependent pathway

Author

Lapalombella, Rosa, Andritsos, Leslie, Liu, Qing, May, Sarah E., Browning, Rebekah, Pham, Lan V., Blum, Kristie A., Blum, William, Ramanunni, Asha, Raymond, Chelsey A., Smith, Lisa L., Lehman, Amy, Mo, Xiaokui, Jarjoura, David, Chen, Ching-Shih, Ford, Richard, Jr, Rader, Christoph, Muthusamy, Natarajan, Johnson, Amy J., and Byrd, John C.

Published
2010
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29. Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents

Author

Deng, Manman, primary, Xu-Monette, Zijun Y., additional, Pham, Lan V., additional, Wang, Xudong, additional, Tzankov, Alexandar, additional, Fang, Xiaosheng, additional, Zhu, Feng, additional, Visco, Carlo, additional, Bhagat, Govind, additional, Dybkaer, Karen, additional, Chiu, April, additional, Tam, Wayne, additional, Zu, Youli, additional, Hsi, Eric D., additional, You, Hua, additional, Huh, Jooryung, additional, Ponzoni, Maurilio, additional, Ferreri, Andrés J.M., additional, Møller, Michael B., additional, Parsons, Benjamin M., additional, Hagemeister, Fredrick, additional, van Krieken, J. Han, additional, Piris, Miguel A., additional, Winter, Jane N., additional, Li, Yong, additional, Xu, Bing, additional, Liu, Phillip, additional, and Young, Ken H., additional

Published
2021
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30. Additional file 1 of XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

Author

Manman Deng, Mingzhi Zhang, Xu-Monette, Zijun Y., Pham, Lan V., Tzankov, Alexandar, Visco, Carlo, Xiaosheng Fang, Bhagat, Govind, Zhu, Feng, Dybkaer, Karen, Chiu, April, Tam, Wayne, Zu, Youli, Hsi, Eric D., Choi, William W. L., Jooryung Huh, Ponzoni, Maurilio, Ferreri, Andrés J. M., Møller, Michael B., Parsons, Benjamin M., J. Han Van Krieken, Piris, Miguel A., Winter, Jane N., Hagemeister, Fredrick, Alinari, Lapo, Li, Yong, Andreeff, Michael, Xu, Bing, and Young, Ken H.

Subjects
immune system diseases, hemic and lymphatic diseases, neoplasms
Abstract

Additional file 1. Table S1: Clinicopathologic and molecular characteristics of DLBCL patients with high or low XPO1 expression. Table S2: Significantly differentially expressed genes between XPO1high and XPO1low DLBCL patients with concurrent TP53 mutation and high MYC expression. Figure S1: Biomarker study for XPO1 and selinexor. (A–B) XPO1high expression showed significant adverse prognostic impact in the ABC subtype but not the GCB subtype of DLBCL. (C) XPO1high expression showed a trend of unfavorable prognostic effect on PFS in MYC-rearranged (MYC-R+) DLBCL. (D) XPO1high expression was associated with significantly poorer survival in DLBCL patients with wild type (Wt) TP53. (E) ABC-DLBCL and GCB-DLBCL cells showed similar sensitivity to the cytotoxicity of selinexor. (F) TP53 mutation (Mut-TP53) significantly reduced the anti-lymphoma efficacy of selinexor in HGBCL-DH cells. IC50 values were calculated by GraphPad Prism 8 based on the cell viability data after 72-hour treatment.

Published
2020
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39. Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma

Author

Zhang, Liang, primary, Yao, Yixin, additional, Zhang, Shaojun, additional, Liu, Yang, additional, Guo, Hui, additional, Ahmed, Makhdum, additional, Bell, Taylor, additional, Zhang, Hui, additional, Han, Guangchun, additional, Lorence, Elizabeth, additional, Badillo, Maria, additional, Zhou, Shouhao, additional, Sun, Yuting, additional, Di Francesco, M. Emilia, additional, Feng, Ningping, additional, Haun, Randy, additional, Lan, Renny, additional, Mackintosh, Samuel G., additional, Mao, Xizeng, additional, Song, Xingzhi, additional, Zhang, Jianhua, additional, Pham, Lan V., additional, Lorenzi, Philip L., additional, Marszalek, Joseph, additional, Heffernan, Tim, additional, Draetta, Giulio, additional, Jones, Philip, additional, Futreal, Andrew, additional, Nomie, Krystle, additional, Wang, Linghua, additional, and Wang, Michael, additional

Published
2019
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40. Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL

Author

Xu-Monette, Ziju Y., primary, Xiao, Min, additional, Au, Qingyan, additional, Padmanabhan, Raghav, additional, Xu, Bing, additional, Hoe, Nicholas, additional, Rodríguez-Perales, Sandra, additional, Torres-Ruiz, Raul, additional, Manyam, Ganiraju C., additional, Visco, Carlo, additional, Miao, Yi, additional, Tan, Xiaohong, additional, Zhang, Hongwei, additional, Tzankov, Alexandar, additional, Wang, Jing, additional, Dybkær, Karen, additional, Tam, Wayne, additional, You, Hua, additional, Bhagat, Govind, additional, Hsi, Eric D., additional, Ponzoni, Maurilio, additional, Ferreri, Andrés J.M., additional, Møller, Michael B., additional, Piris, Miguel A., additional, van Krieken, J. Han, additional, Winter, Jane N., additional, Westin, Jason R., additional, Pham, Lan V., additional, Medeiros, L. Jeffrey, additional, Rassidakis, George Z., additional, Li, Yong, additional, Freeman, Gordon J., additional, and Young, Ken H., additional

Published
2019
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42. Pharmacoproteomics Identifies PLK1 As Vulnerability for Aggressive B-Cell Lymphomas

Author

Ren, Yuan, primary, Bi, Chengfeng, additional, Zhao, Xiaohong, additional, Lwin, Tint, additional, Cheng, Wang, additional, Yuan, Ji, additional, Siqueira Silva, Ariosto, additional, Shah, Bijal D., additional, Fang, Bin, additional, Li, Tao, additional, Koomen, John M., additional, Jiang, Huijuan, additional, Chavez, Julio C., additional, Pham, Lan V., additional, Sudalagunta, Praneeth Reddy, additional, Wan, Lixin, additional, Wang, Xuefeng, additional, Dalton, William S., additional, Moscinski, Lynn C., additional, Shain, Kenneth H., additional, Vose, Julie M., additional, Cleveland, John, additional, Sotomayor, Eduardo, additional, Fu, Kai, additional, and Tao, Jianguo, additional

Published
2018
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43. Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Author

Pham, Lan V., primary, Huang, Shengjian, additional, Zhang, Hui, additional, Zhang, Jun, additional, Bell, Taylor, additional, Zhou, Shouhao, additional, Pogue, Elizabeth, additional, Ding, Zhiyong, additional, Lam, Laura, additional, Westin, Jason, additional, Davis, R. Eric, additional, Young, Ken H., additional, Medeiros, L. Jeffrey, additional, Ford, Richard J., additional, Nomie, Krystle, additional, Zhang, Leo, additional, and Wang, Michael, additional

Published
2018
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45. Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma

Author

Liu, Wei, primary, Chen, Juan, additional, Tamayo, Archito T., additional, Ruan, Changgeng, additional, Li, Li, additional, Zhou, Shouhao, additional, Shen, Chan, additional, Young, Ken H., additional, Westin, Jason, additional, Davis, Richard E., additional, Hu, Shimin, additional, Medeiros, Leonard J., additional, Ford, Richard J., additional, and Pham, Lan V., additional

Published
2017
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46. AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma

Author

Wang, Jinfen, primary, Xu-Monette, Zijun Y., additional, Jabbar, Kausar J., additional, Shen, Qi, additional, Manyam, Ganiraju C., additional, Tzankov, Alexandar, additional, Visco, Carlo, additional, Wang, Jing, additional, Montes-Moreno, Santiago, additional, Dybkær, Karen, additional, Tam, Wayne, additional, Bhagat, Govind, additional, Hsi, Eric D., additional, van Krieken, J. Han, additional, Ponzoni, Maurilio, additional, Ferreri, Andrés J.M., additional, Wang, Shi, additional, Møller, Michael B., additional, Piris, Miguel A., additional, Medeiros, L. Jeffrey, additional, Li, Yong, additional, Pham, Lan V., additional, and Young, Ken H., additional

Published
2017
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47. RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma

Author

Zhang, Mingzhi, primary, Xu-Monette, Zijun Y., additional, Li, Ling, additional, Manyam, Ganiraju C., additional, Visco, Carlo, additional, Tzankov, Alexandar, additional, Wang, Jing, additional, Montes-Moreno, Santiago, additional, Dybkaer, Karen, additional, Chiu, April, additional, Orazi, Attilio, additional, Zu, Youli, additional, Bhagat, Govind, additional, Richards, Kristy L., additional, Hsi, Eric D., additional, Choi, William W.L., additional, Han van Krieken, J., additional, Huh, Jooryung, additional, Ponzoni, Maurilio, additional, Ferreri, Andrés J.M., additional, Møller, Michael B., additional, Parsons, Ben M., additional, Winter, Jane N., additional, Piris, Miguel A., additional, Medeiros, L. Jeffrey, additional, Pham, Lan V., additional, and Young, Ken H., additional

Published
2016
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48. CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma

Author

Mohanty, Atish, primary, Sandoval, Natalie, additional, Das, Manasi, additional, Pillai, Raju, additional, Chen, Lu, additional, Chen, Robert W., additional, Amin, Hesham M., additional, Wang, Michael, additional, Marcucci, Guido, additional, Weisenburger, Dennis D., additional, Rosen, Steven T., additional, Pham, Lan V., additional, and Ngo, Vu N., additional

Published
2016
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49. Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma

Author

Pham, Lan V., primary, Bryant, Jerry L., additional, Mendez, Richard, additional, Chen, Juan, additional, Tamayo, Archito T., additional, Xu-Monette, Zijun Y., additional, Young, Ken H., additional, Manyam, Ganiraju C., additional, Yang, David, additional, Medeiros, L. Jeffrey, additional, and Ford, Richard J., additional

Published
2016
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50. <html>Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma</html>

Author

Young, Ken H., Piris, Miguel A., Ferreri, Andrés J.M., van Krieken, J. Han, Huh, Jooryung, Ponzoni, Maurilio, Xu-Monette, Zijun Y., Zu, Youli, Hsi, Eric D., Richards, Kristy L., Jeffrey Medeiros, L., Møller, Michael B., Ok, Chi Young, Montes-Moreno, Santiago, Manyam, Ganiraju C., Chiu, April, Dybkaer, Karen, Tzankov, Alexandar, Wang, Jinfen, Parsons, Ben M., Visco, Carlo, Choi, William W.L., Winter, Jane N., Li, Ling, Pham, Lan V., Zhang, Mingzhi, Sun, Ruifang, Orazi, Attilio, and Bhagat, Govind

Subjects
animal structures, hemic and lymphatic diseases
Abstract

Dysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2− activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications.

Published
2015
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