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

460 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

Keywords

Adaptor Proteins, Signal Transducing
Adenine/analogs & derivatives
Animals
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Blotting, Western
Cell Line, Tumor
DNA-Binding Proteins/genetics
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic/drug effects
Gene Regulatory Networks/drug effects
Humans
Interferon Regulatory Factors/genetics
Interferon-beta/genetics
Lenalidomide
Lymphoma, Large B-Cell, Diffuse/drug therapy
Mice
Mice, Inbred NOD
Mice, SCID
NF-kappa B/genetics
Peptide Hydrolases/genetics
Piperidines
Pyrazoles/administration & dosage
Pyrimidines/administration & dosage
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction/drug effects
Thalidomide/administration & dosage
Transcription Factors/genetics
Tumor Burden/drug effects
Ubiquitin-Protein Ligases
Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccr.2012.05.024

Cite this

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.",

keywords = "Adaptor Proteins, Signal Transducing, Adenine/analogs \& derivatives, Animals, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Blotting, Western, Cell Line, Tumor, DNA-Binding Proteins/genetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic/drug effects, Gene Regulatory Networks/drug effects, Humans, Interferon Regulatory Factors/genetics, Interferon-beta/genetics, Lenalidomide, Lymphoma, Large B-Cell, Diffuse/drug therapy, Mice, Mice, Inbred NOD, Mice, SCID, NF-kappa B/genetics, Peptide Hydrolases/genetics, Piperidines, Pyrazoles/administration \& dosage, Pyrimidines/administration \& dosage, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/drug effects, Thalidomide/administration \& dosage, Transcription Factors/genetics, Tumor Burden/drug effects, Ubiquitin-Protein Ligases, Xenograft Model Antitumor Assays",

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",

language = "English",

volume = "21",

pages = "723--737",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

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.

KW - Adaptor Proteins, Signal Transducing

KW - Adenine/analogs & derivatives

KW - Animals

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Blotting, Western

KW - Cell Line, Tumor

KW - DNA-Binding Proteins/genetics

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Gene Regulatory Networks/drug effects

KW - Humans

KW - Interferon Regulatory Factors/genetics

KW - Interferon-beta/genetics

KW - Lenalidomide

KW - Lymphoma, Large B-Cell, Diffuse/drug therapy

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - NF-kappa B/genetics

KW - Peptide Hydrolases/genetics

KW - Piperidines

KW - Pyrazoles/administration & dosage

KW - Pyrimidines/administration & dosage

KW - RNA Interference

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Signal Transduction/drug effects

KW - Thalidomide/administration & dosage

KW - Transcription Factors/genetics

KW - Tumor Burden/drug effects

KW - Ubiquitin-Protein Ligases

KW - Xenograft Model Antitumor Assays

UR - https://www.scopus.com/pages/publications/84862152044

U2 - 10.1016/j.ccr.2012.05.024

DO - 10.1016/j.ccr.2012.05.024

M3 - Article

C2 - 22698399

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

Keywords

UN SDGs

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