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| Status |
Public on Nov 03, 2017 |
| Title |
Oncolytic reactivation of KSHV as a therapeutic approach for primary effusion lymphoma: RNA-sequencing of PEL cell lines during KSHV reactivation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi’s sarcoma-associated herpesvirus infection, which is most commonly seen in HIV-positive patients. Induction of HIV reactivation by external stimuli in the presence of highly active anti-retroviral therapy (HAART) has been examined for its efficacy to eradicate latently infected HIV. Similary, lytic activation of viruses from latently infected tumor cells with anti-cancer drugs represents an effective strategy of anti-neoplastic therapy, through the induction of oncolysis by viral replication, stimulation of immune responses to the viral lytic antigens, and intrinsic effects of cancer drugs. Here we examined the combination of PEP005 with epigenetic drugs as a rational therapeutic strategy to target both in AIDS-associated KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal protein (BET) inhibitor, in combination with a FDA-approved drug, PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL-6 and VEGF production from PEL cells. This combination has been proposed for use in reactivation of HIV from latently infected T-cells, and the same combination and dosage inhibited PEL growth in vitro and delayed tumor growth in a PEL xenograft tumor model. Downstream activation of NF-B by PEP005 combined with sequestration of bromodomain-containing protein 4 (BRD4) by JQ1 robustly increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. We suggest that the combination of PEP005 with JQ1 should be considered as a rational therapeutic approach for HIV-associated PEL.
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| Overall design |
A total of 12 samples were analyzed in this study. The study included three primary effusion lymphoma (PEL) cell lines, BC3, BCBL-1, HBL-6. Individual cultures of each cell line were cultured in medium containing vehicle control (DMSO), JQ1, PEP005, or the combination (JQ1 + PEP005). Following treatment of the cells for 24 hours, total RNA was isolated and then submitted fro RNA-sequencing analysis.
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| Contributor(s) |
Izumiya Y, Zhou F, Tepper CG |
| Citation(s) |
28847988 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| P30 CA093373 |
Cancer Center Support Grant P30 |
UNIVERSITY OF CALIFORNIA DAVIS |
PRIMO N. LARA |
| R01 DE025985 |
KSHV Replication in Oral Epithelial Cells |
UNIVERSITY OF CALIFORNIA DAVIS |
Yoshihiro Izumiya |
| DP2 OD008752 |
Investigation and Development of New Therapeutic Avenues for Scleroderma |
UNIVERSITY OF CALIFORNIA DAVIS |
Emanual M. Maverakis |
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| Submission date |
Nov 03, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Clifford G. Tepper |
| E-mail(s) |
cgtepper@ucdavis.edu
|
| Phone |
916-734-7195
|
| Organization name |
UC Davis School of Medicine
|
| Department |
Biochemistry and Molecular Medicine
|
| Street address |
4645 2nd Avenue, Room 2300A
|
| City |
Sacramento |
| State/province |
CA |
| ZIP/Postal code |
95817 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA352335 |
| SRA |
SRP092520 |
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