Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma.
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.
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yibin
Y
Yang
Arthur L
AL
Shaffer
N C Tolga
NC
Emre
Michele
M
Ceribelli
Meili
M
Zhang
George
G
Wright
Wenming
W
Xiao
John
J
Powell
John
J
Platig
Holger
H
Kohlhammer
Ryan M
RM
Young
Hong
H
Zhao
Yandan
Y
Yang
Weihong
W
Xu
Joseph J
JJ
Buggy
Sriram
S
Balasubramanian
Lesley A
LA
Mathews
Paul
P
Shinn
Rajarshi
R
Guha
Marc
M
Ferrer
Craig
C
Thomas
Thomas A
TA
Waldmann
Louis M
LM
Staudt
D048868:Adaptor Proteins, Signal Transducing; D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays; D000099218:Interferon Regulatory Factor-4
D048868:Adaptor Proteins, Signal Transducing; D000225:Adenine; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D000077269:Lenalidomide; D016328:NF-kappa B; D010447:Peptide Hydrolases; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D013792:Thalidomide; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4; C502543:CRBN protein, human; C076877:SPIB protein, human; C551803:ibrutinib