Zuzana Prouzová

Suppression of the LMP2A target gene, EGR‐1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle

Hodgkins lymphoma is unusual among B cell lymphomas, in so far as the malignant Hodgkin/Reed–Sternberg (HRS) cells lack a functional B cell receptor (BCR), as well as many of the required downstream signalling components. In Epstein–Barr virus (EBV)‐positive cases of Hodgkins lymphoma, HRS cells express the viral latent membrane proteins (LMP)‐1 and ‐2A. LMP2A is thought to contribute to the pathogenesis of Hodgkins lymphoma by providing a surrogate BCR‐like survival signal. However, LMP2A has also been shown to induce the virus‐replicative cycle in B cells, an event presumably incompatible with lymphomagenesis. In an attempt to resolve this apparent paradox, we compared the transcriptional changes observed in primary HRS cells with those induced by LMP2A and by BCR activation in primary human germinal centre (GC) B cells, the presumed progenitors of HRS cells. We found a subset of genes that were up‐regulated by both LMP2A expression and BCR activation but which were down‐regulated in primary HRS cells. These genes included EGR1, an immediate‐early gene that is required for BCR‐induced entry to the virus‐replicative cycle. We present data supporting a model for the pathogenesis of EBV‐positive Hodgkins lymphoma in which LMP2A‐expressing HRS cells lacking BCR signalling functions cannot induce EGR1 and are consequently protected from entry to the virus lytic cycle. The primary microarray data are available from GEO (http://www.ncbi.nlm.nih.gov/geo/) under series Accession No 46143. Copyright

“Sun Ray” Appearance in a Case of Cardiac Angiosarcoma: A Comparison of MRI and PET/CT

Our article reports a case of a 35-year-old man with cardiac mass, who underwent a wide range of imaging methods, including cardiac magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). Contrast-enhanced MRI images revealed “sun ray” pattern in the mass. Final histopathological diagnosis of angiosarcoma was confirmed during autopsy. To our knowledge, our case is the second direct observation of this MRI diagnostic pattern and the first one that allows a comparison with PET/CT findings.

miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

DOWN‐REGULATION OF MIR‐150 AND UP‐REGULATION OF ITS TARGET FOXP1 IS ASSOCIATED WITH TRANSFORMATION OF FOLLICULAR LYMPHOMA

Down-regulation of miR-150 and up-regulation of its target FOXP1 is associated with transformation of follicular lymphoma.Down-regulation of miR-150 and up-regulation of its target FOXP1 is associated with transformation of follicular lymphoma.

Abstract 1479: Differential expression of microRNAs in transformation of follicular lymphoma to diffuse large B cell lymphoma

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, and are frequently aberrantly expressed in cancer. We aimed to understand their role in the transformation of indolent follicular lymphoma (FL) into an aggressive diffuse large B cell lymphoma. This happens in ~3% of cases per year during the course of the disease, and is associated with median survival of only 2 years. The NGS revealed number of aberrations associated with transformed FL (tFL), including frequent high-level activity of MYC (amplifications, translocations, and mutations) or loss of DNA damage regulators (p53, CDKN2A/B). Firstly, we performed a miRNA profiling (TaqMan miRNA Arrays) in paired FL and tFL samples (N=8 pairs). This revealed a relatively small group of 5 miRNAs that are consistently differentially expressed in tFL (P 1.5). Since the most frequently acquired aberration in tFL is the high-level activity of MYC we performed a correlation analysis of MYC levels and expression of these miRNAs in additional samples of FL, tFL, and CLL samples with/without MYC duplication (N=40 FL/tFL, N=39 CLL). This revealed that at least one of these miRNAs is significantly down-modulated (P Citation Format: Katerina Musilova, Gabriela Pavlasova, Vaclav Seda, Eva Vojackova, Katerina Cerna, Veronika Svobodova, Robert Pytlik, Vit Prochazka, Zuzana Prouzova, Sarka Pospisilova, Lenka Zlamalikova, Heidi Mocikova, Lenka Kruzova, Marie Jarosova, Andrew Evans, Clive Zent, Leos Kren, Marek Trneny, Jiri Mayer, Andrea Janikova, Marek Mraz. Differential expression of microRNAs in transformation of follicular lymphoma to diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1479. doi:10.1158/1538-7445.AM2017-1479