Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

Yibin Yang; Arthur L. Shaffer; N. C.Tolga Emre; Michele Ceribelli; Meili Zhang; George Wright; Wenming Xiao; John Powell; John Platig; Holger Kohlhammer; Ryan M. Young; Hong Zhao; Yandan Yang; Weihong Xu; Joseph J. Buggy; Sriram Balasubramanian; Lesley A. Mathews; Paul Shinn; Rajarshi Guha; Marc Ferrer; Craig Thomas; Thomas A. Waldmann; Louis M. Staudt

doi:10.1016/j.ccr.2012.05.024

Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

Yibin Yang, Arthur L. Shaffer, N. C.Tolga Emre, Michele Ceribelli, Meili Zhang, George Wright, Wenming Xiao, John Powell, John Platig, Holger Kohlhammer, Ryan M. Young, Hong Zhao, Yandan Yang, Weihong Xu, Joseph J. Buggy, Sriram Balasubramanian, Lesley A. Mathews, Paul Shinn, Rajarshi Guha, Marc FerrerCraig Thomas, Thomas A. Waldmann, Louis M. Staudt

Research output: Contribution to journal › Article › peer-review

441 Scopus citations

Abstract

Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

Original language	English
Pages (from-to)	723-737
Number of pages	15
Journal	Cancer Cell
Volume	21
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2012.05.024
State	Published - Jun 12 2012
Externally published	Yes

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Yang, Y., Shaffer, A. L., Emre, N. C. T., Ceribelli, M., Zhang, M., Wright, G., Xiao, W., Powell, J., Platig, J., Kohlhammer, H., Young, R. M., Zhao, H., Yang, Y., Xu, W., Buggy, J. J., Balasubramanian, S., Mathews, L. A., Shinn, P., Guha, R., ... Staudt, L. M. (2012). Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma. Cancer Cell, 21(6), 723-737. https://doi.org/10.1016/j.ccr.2012.05.024

@article{25000424bf8e42faaddc8f0855fe1543,

title = "Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma",

abstract = "Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.",

author = "Yibin Yang and Shaffer, {Arthur L.} and Emre, {N. C.Tolga} and Michele Ceribelli and Meili Zhang and George Wright and Wenming Xiao and John Powell and John Platig and Holger Kohlhammer and Young, {Ryan M.} and Hong Zhao and Yandan Yang and Weihong Xu and Buggy, {Joseph J.} and Sriram Balasubramanian and Mathews, {Lesley A.} and Paul Shinn and Rajarshi Guha and Marc Ferrer and Craig Thomas and Waldmann, {Thomas A.} and Staudt, {Louis M.}",

year = "2012",

month = jun,

day = "12",

doi = "10.1016/j.ccr.2012.05.024",

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Yang, Y, Shaffer, AL, Emre, NCT, Ceribelli, M, Zhang, M, Wright, G, Xiao, W, Powell, J, Platig, J, Kohlhammer, H, Young, RM, Zhao, H, Yang, Y, Xu, W, Buggy, JJ, Balasubramanian, S, Mathews, LA, Shinn, P, Guha, R, Ferrer, M, Thomas, C, Waldmann, TA & Staudt, LM 2012, 'Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma', Cancer Cell, vol. 21, no. 6, pp. 723-737. https://doi.org/10.1016/j.ccr.2012.05.024

TY - JOUR

T1 - Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

AU - Yang, Yibin

AU - Shaffer, Arthur L.

AU - Emre, N. C.Tolga

AU - Ceribelli, Michele

AU - Zhang, Meili

AU - Wright, George

AU - Xiao, Wenming

AU - Powell, John

AU - Platig, John

AU - Kohlhammer, Holger

AU - Young, Ryan M.

AU - Zhao, Hong

AU - Yang, Yandan

AU - Xu, Weihong

AU - Buggy, Joseph J.

AU - Balasubramanian, Sriram

AU - Mathews, Lesley A.

AU - Shinn, Paul

AU - Guha, Rajarshi

AU - Ferrer, Marc

AU - Thomas, Craig

AU - Waldmann, Thomas A.

AU - Staudt, Louis M.

PY - 2012/6/12

Y1 - 2012/6/12

N2 - Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

AB - Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

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AN - SCOPUS:84862152044

SN - 1535-6108

VL - 21

SP - 723

EP - 737

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

Abstract

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