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| Status |
Public on Aug 16, 2012 |
| Title |
Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Knowledge of essential oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells bearing an oncogenic mutation while sparing normal cells. Lenalidomide is emerging as an active agent in diffuse large B cell lymphoma (DLBCL), especially for the activated B cell-like (ABC) subtype, but the mechanism of its action is unknown. Here we show that lenalidomide kills ABC DLBCL cells by augmenting the production of interferon 3/4, which these cells are predisposed to produce by their oncogenic MYD88 mutations. Lenalidomide stimulates the type I interferon pathway by suppressing IRF4, a repressor of IRF7. IRF4 is required for ABC DLBCL viability and is both a target and an amplifier of NF-kB signaling in this lymphoma subtype. Blockade of B cell receptor (BCR) signaling synergized with lenalidomide to reduce IRF4 levels, increase interferon 3/4 secretion, decrease NF-kB, and kill ABC DLBCL cells, suggesting therapeutic combinations that exploit the oncogenic signaling pathways in this cancer.
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| Overall design |
For the OCILY10 cell line treated with 10 uM lenalidamide, a four point time course of 3, 6, 24, and 48 hours was analyzed (n=4). For the TMD8 cell line treated with 10 uM lenalidamide, a four point time course of 3, 6, 24, and 48 hours was analyzed (n=4).
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| |
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| Citation(s) |
22698399 |
| Submission date |
Oct 17, 2011 |
| Last update date |
Feb 22, 2018 |
| Contact name |
Louis M. Staudt |
| E-mail(s) |
lstaudt@mail.nih.gov
|
| Phone |
301-402-1892
|
| Organization name |
National Cancer Institute
|
| Department |
Lymphoid Malignancies Branch
|
| Lab |
Louis M Staudt
|
| Street address |
9000 Rockville Pike, Bldg 10, Rm 4N114
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL4133 |
Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) |
|
| Samples (8)
|
| GSM818428 |
OCILY10 Lenalidamide -3 hours - mAdbID:107900 |
| GSM818429 |
OCILY10 Lenalidamide -6 hours - mAdbID:107901 |
| GSM818430 |
OCILY10 Lenalidamide -24 hours - mAdbID:107902 |
| GSM818431 |
OCILY10 Lenalidamide -48 hours - mAdbID:107903 |
| GSM818432 |
TMD8 Lenalidamide -24 hours - mAdbID:107904 |
| GSM818433 |
TMD8 Lenalidamide -48 hours - mAdbID:107905 |
| GSM818434 |
TMD8 Lenalidamide -3 hours - mAdbID:108494 |
| GSM818435 |
TMD8 Lenalidamide -6 hours - mAdbID:108495 |
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| Relations |
| BioProject |
PRJNA148037 |
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