VIRALLY-INDUCED HEMATOLOGICAL MALIGNANCIES WITH DISMAL PROGNOSIS: IMPACT OF EPIGENETICS AND POTENTIAL THERAPEUTICS

Abstract

Blood malignancies are a heterogeneous group of cancer affecting blood cells or their hematopoiesis, and are the leading cause of increased mortality rates worldwide. The molecular mechanisms dictating oncogenesis and the currently used therapeutic approaches still present many gaps and require further understanding, to increase the overall survival of patients and alleviate the burden of these malignancies. In this manuscript, we tackled two virally driven hematological malignancies having a dismal prognosis and associated with chemo-resistance and high relapse rates.

Primary effusion lymphoma (PEL) is a rare aggressive subset of non‐Hodgkin B cell lymphoma. PEL is secondary to Kaposi sarcoma herpes virus (KSHV) and predominantly develops in serous cavities. Current treatment modalities depend on aggressive chemotherapy, yet fail to achieve long lasting remission or to improve overall survival in PEL patients. Lenalidomide (Lena) is an immune-modulatory drug, which exhibits anti-proliferative effects on PEL cell lines. Arsenic trioxide (ATO) proved efficient when used as a combination therapy to treat multiple blood malignancies, including PEL. We demonstrated that ATO/Lena enhanced survival of PEL mice, decreased peritoneal ascites volume, and suppressed tumor organ infiltration. In ex vivo ascites-derived PEL cells, ATO/Lena inhibited cell growth, downregulated latent viral proteins, and decreased NF‐κB activation. This was associated with decreased cytokine production and lytic reactivation leading to apoptosis. Our results elucidate the mechanism of action of ATO/Lena and present it as a promising targeted therapeutic modality in PEL management, which warrants further clinical investigation.

Adult T cell leukemia (ATL) is an aggressive T-cell malignancy associated with the human T-cell leukemia virus type 1 (HTLV-1). ATL associates with dismal prognosis and develops after a long latency period, following accumulation of multiple genetic and epigenetic alterations. Two viral proteins, Tax and HBZ, play central roles in ATL leukemogenesis. Tax oncoprotein transforms T cells in vitro, induces ATL-like disease in mice, and a rough eye phenotype in Drosophila melanogaster, indicative of transformation. Among multiple functions, Tax modulates the expression of the enhancer of zeste homolog 2 (EZH2), a methyltransferase of the Polycomb Repressive Complex 2 (PRC2), leading to H3K27me3-dependent reprogramming of around half of cellular genes. HBZ is a negative regulator of Tax-mediated viral transcription. HBZ effects on epigenetic signatures are underexplored. In this work, we established an hbz transgenic fly model, and demonstrated that, unlike Tax, which induces NF-κB activation and enhances PRC2 activity creating an activation loop, HBZ neither induces transformation nor NF-κB activation in vivo. However, overexpression of Tax or HBZ increases the PRC2 activity. Moreover, we report a novel interaction between HBZ and polycomb core components EZH2 and SUZ12 resulting in upregulation of H3K27me3, a repressive transcription hallmark. Importantly, overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB or PRC2 activation and totally rescues Tax-induced transformation and senescence. Our results establish the in vivo antagonistic effect of HBZ on Tax-induced transformation and cellular effects, and opens perspectives for new therapeutic strategies targeting the epigenetic machinery in ATL. Overall, our work proposed a promising therapeutic approach for PEL and offered a better molecular understanding on viral transformation in ATL.