Research

Kaposi's sarcoma-associated herpesvirus (KSHV) causes cancer, most commonly in immuno-compromised individuals. The clinically most relevant KSHV-induced disease is Kaposi's sarcoma (KS), a complex tumor driven by KSHV-infected endothelial cells. Due to the AIDS epidemic, KS has become the most common cancer in parts of Africa. KSHV also infects B lymphocytes and can consequently cause B cell lymphomas, including primary effusion lymphoma (PEL). KSHV constitutively expresses viral microRNAs from 12 precursors, suggesting a role of these microRNAs in viral replication and pathogenesis.

Most of our datasets are available through our publications, but several of our additional datasets can be downloaded on our Data page.

Research Areas

KSHV miRNAs

MicroRNAs are ~22 nucleotide regulatory RNAs expressed by animals, plants and some viruses, particularly herpesviruses. As components of the RNA-induced silencing complex (RISC), microRNAs guide the repression of mRNAs bearing sequences with partial complementarity to the microRNA. This effect is most commonly mediated through base pairing between the "seed region" of the microRNA, spanning nucleotides 2-7, and sites located in the 3'UTRs of target mRNAs. Because there are several hundred known mammalian microRNAs and each can regulate several hundred mRNAs, it is now thought that most mRNAs are regulated by microRNAs in some biological context. Our lab is currently pursuing the identification of mRNA targets and functions of the KSHV microRNAs in primary effusion lymphoma cell lines and KSHV-infected endothelial cells.

KSHV-mediated B cell transformation in Primary Effusion Lymphoma

To understand which cellular genes are required for KSHV-mediated B cell transformation in PEL, we performed genome-wide CRISPR essentiality screens across a panel of eight PEL cell lines (Manzano et al., Nature Communications 2018). Comparisons with a total of 15 other cancer types allowed us to distinguish genes that are essential in most cancers from genes that are more specifically essential in PEL. Our results and extensive validation identified the hematopoietic lineage transcription factor interferon regulatory factor 4 (IRF4), cyclin D2, MDM2, MCL1 and cellular FLIP as novel essential genes in PEL cells. Importantly, dependencies on IRF4, MDM2, cyclin D2, and MCL1 are druggable, using inhibitors already in the clinic or in pre-clinical development. Altogether, this study arrived at a comprehensive understanding of the cellular genes and pathways that are critical in PEL and directly identifies novel strategies for therapeutic intervention in this currently incurable cancer. In our ongoing work, we focus on KSHV-mediated regulation of the identified essential genes.

Mechanisms of KSHV-mediated endothelial cell deregulation

We are currently studying the role of the KSHV miRNAs in de novo KSHV-infected human endothelial cells. We are particularly interested in the KSHV miR-K10 miRNAs, which we have shown to function as viral mimics of cellular miR-142-3p (Cell Host and Microbe 2011 and RNA 2015), a miRNA that is not normally expressed in endothelial cells. We hypothesize that KSHV-mediated introduction of miR-142-3p-like activity into endothelial cells contributes to their deregulation in the context of KSHV infection.

Drug targets in KSHV-associated malignancies

Our studies in the B cell model have identified several new ways to potentially target PEL. We have particularly focused on the mechanism of action of immunomodulatory drugs (IMiDs) in PEL. This work was initially prompted by the invariant essentiality of IRF4 in PEL and is described in two recent publications (Blood 2018 and Blood Advances 2019). This work suggests that the mechanisms of IMiDs in PEL is still incompletely understood, but supports the further development of IMiDs for therapeutic intervention in PEL.