Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). The cellular transcription factor (TF) interferon (IFN) regulatory factor 4 (IRF4) is an essential oncogene in PEL, but its specific role in PEL and how KSHV deregulates IRF4 remain unknown. Here, we report that the KSHV latency protein viral interferon regulatory factor 3 (vIRF3) cooperates with IRF4 and cellular BATF (basic leucine zipper ATF-like TF) to drive a super-enhancer (SE)-mediated oncogenic transcriptional program in PEL. Chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) experiments demonstrated that IRF4, vIRF3, and BATF cooccupy the SEs of key survival genes, in a pattern that is distinct from those seen with other IRF4-driven malignancies. All three proteins cooperatively drive SE-mediated IRF4 overexpression. Inactivation of vIRF3 and, to a lesser extent, BATF phenocopies the gene expression changes and loss of cellular viability observed upon inactivation of IRF4. In sum, this work suggests that KSHV vIRF3 and cellular IRF4 and BATF cooperate as oncogenic transcription factors on SEs to promote cellular survival and proliferation in KSHV-associated lymphomas.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) causes the aggressive disease primary effusion lymphoma (PEL). Here, we show that a viral transcription factor (vIRF3) cooperates with the cellular transcription factor IRF4 to control an oncogenic gene expression program in PEL cells. These proteins promote KSHV-mediated B cell transformation by activating the expression of prosurvival genes through super-enhancers. Our report thus demonstrates that this DNA tumor virus encodes a transcription factor that functions with cellular IRF4 to drive oncogenic transcriptional reprogramming.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL)
interferon regulatory factor 4 (IRF4) in PEL should be required for the survival of PEL cell lines, we examined the expression and essentiality of established IRF4 co-transcription factor (TF) in our published CRISPR gene essentiality screens [21]
On the basis of our hypothesis that IRF4, viral interferon regulatory factor 3 (vIRF3), and BATF function on SEs to drive the expression of essential oncogenes in PEL cells, we investigated the regulation of the 712 genes we had previously designated essential in PEL cells in our mRNA-Seq data sets
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). We report that the KSHV latency protein viral interferon regulatory factor 3 (vIRF3) cooperates with IRF4 and cellular BATF (basic leucine zipper ATF-like TF) to drive a super-enhancer (SE)-mediated oncogenic transcriptional program in PEL. PSODs are genes that are essential in most or all PEL cell lines but are unlikely to be required for the survival of all other cancer cell types These analyses revealed a uniform dependency of PEL cells on the lymphoid transcription factor (TF) interferon regulatory factor 4 (IRF4). IRF4 is essential in lymphoblastoid cell lines (LCLs [29, 30]), which result from in vitro transformation of B cells by EBV In these other settings, IRF4 binds to enhancers, including tightly clustered enhancers referred to as “super-enhancers” (SEs), to drive overexpression of MYC or, in ATLL, the essential IRF4 cotranscription factor BATF3 (basic leucine zipper ATF-like TF 3 [27, 31–34]). While BET inhibitors have known high toxicity in PEL cells [35, 38], the identity and regulation of SEs in PEL cells have not been studied
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