Antineoplastic effects of liposomal short interfering RNA treatment targeting BLIMP1/PRDM1 in primary effusion lymphoma

Riva, Giovanni; Lagreca, Ivana; Mattiolo, Adriana; Belletti, Daniela; Lignitto, Laura; Barozzi, Patrizia; Ruozi, Barbara; Vallerini, Daniela; Quadrelli, Chiara; Corradini, Giorgia; Forghieri, Fabio; Marasca, Roberto; Narni, Franco; Tosi, Giovanni; Forni, Flavio; Vandelli, Maria Angela; Amadori, Alberto; Chieco‐Bianchi, Luigi; Potenza, Leonardo; Calabrò, Maria Luisa; Luppi, Mario

doi:10.3324/haematol.2015.126854

Cited by 9 publications

(7 citation statements)

References 15 publications

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“…PRDM1 is highly expressed in PEL cells compared with other B cell lymphomas 35 . siRNA silencing of PRDM1 greatly reduced PEL cell growth 36 , 37 . H3K27ac HiChIP linked the PRDM1 promoter to >10 enhancer sites ~600 kb upstream and ~22 kb downstream of the PRDM1 promoter (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Wang

Zhang

et al. 2020

Nat Commun

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Primary effusion lymphoma (PEL) has a very poor prognosis. To evaluate the contributions of enhancers/promoters interactions to PEL cell growth and survival, here we produce H3K27ac HiChIP datasets in PEL cells. This allows us to generate the PEL enhancer connectome, which links enhancers and promoters in PEL genome-wide. We identify more than 8000 genomic interactions in each PEL cell line. By incorporating HiChIP data with H3K27ac ChIP-seq data, we identify interactions between enhancers/enhancers, enhancers/promoters, and promoters/promoters. HiChIP further links PEL super-enhancers to PEL dependency factors MYC, IRF4, MCL1, CCND2, MDM2, and CFLAR. CRISPR knock out of MEF2C and IRF4 significantly reduces MYC and IRF4 super-enhancer H3K27ac signal. Knock out also reduces MYC and IRF4 expression. CRISPRi perturbation of these super-enhancers by tethering transcription repressors to enhancers significantly reduces target gene expression and reduces PEL cell growth. These data provide insights into PEL molecular pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Wang

Zhang

et al. 2020

Nat Commun

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“…Enhanced expression of EBV lytic genes has also been observed in coinfected PEL cells, which can be attributed to an increased expression of the transcription factor BLIMP1 [ 23 ]. BLIMP1 is involved not only in the maintenance of PEL [ 24 ] but also in the induction of both EBV immediate early genes BZLF1 and BRLF1 [ 25 ]. The expression of BLIMP1 marks the end of the GCR, sending GC B cells into antibody-producing plasma cells, which correlates with EBV reactivation [ 26 ].…”

Section: Ebv and Kshv Coinfect B Cells In Primary Effusion Lymphoma (Pel) And Germinotropic Lpdmentioning

confidence: 99%

The Role of Coinfections in the EBV–Host Broken Equilibrium

Sánchez-Ponce

Fuentes‐Pananá

2021

Viruses

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The Epstein–Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)—an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to synergize or cooperate with these agents to trigger or worsen the disease.

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“…84 On the basis of the normal counterpart of PEL being post-germinal center B cells with plasmablastic differentiation, treatments using liposome-modified B-lymphocyte-induced maturation protein 1 small interfering RNA and immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide are being developed. 47,85 IMiDs are recognized as promising drugs in terms of their antiproliferative effects against the majority of PEL cell lines within clinically achievable concentrations by cell cycle arrest without any induction of lytic cycle reactivation. IMiDs suppressed IRF4 in a cereblon-dependent manner, resulting in rapid degradation of Ikaros (IKZF1), but not Aiolos (IKZF3), in PEL cell lines.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Biology and management of primary effusion lymphoma

Shimada

Hayakawa

Kiyoi

2018

Blood

103

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Primary effusion lymphoma (PEL) is a rare B-cell malignancy that most often occurs in immunocompromised patients, such as HIV-infected individuals and patients receiving organ transplantation. The main characteristic of PEL is neoplastic effusions in body cavities without detectable tumor masses. The onset of the disease is associated with latent infection of human herpes virus 8/Kaposi sarcoma-associated herpes virus, and the normal counterpart of tumor cells is B cells with plasmablastic differentiation. A condition of immunodeficiency and a usual absence of CD20 expression lead to the expectation of the lack of efficacy of anti-CD20 monoclonal antibody; clinical outcomes of the disease remain extremely poor, with an overall survival at 1 year of ∼30%. Although recent progress in antiretroviral therapy has improved outcomes of HIV-infected patients, its benefit is still limited in patients with PEL. Furthermore, the usual high expression of programmed death ligand 1 in tumor cells, one of the most important immune-checkpoint molecules, results in the immune escape of tumor cells from the host immune defense, which could be the underlying mechanism of poor treatment efficacy. Molecular-targeted therapies for the activating pathways in PEL, including NF-κB, JAK/STAT, and phosphatidylinositol 3-kinase/AKT, have emerged to treat this intractable disease. A combination of immunological recovery from immune deficiency, overcoming the immune escape, and the development of more effective drugs will be vital for improving the outcomes of PEL patients in the future.

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Antineoplastic effects of liposomal short interfering RNA treatment targeting BLIMP1/PRDM1 in primary effusion lymphoma

Abstract: LETTERS TO THE EDITOR© F e r r a t a S t o r t i F o u n d a t i o n

Cited by 9 publications

References 15 publications

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

The Role of Coinfections in the EBV–Host Broken Equilibrium

Biology and management of primary effusion lymphoma

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