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Musilova, Katerina;
Pavlasova, Gabriela;
Seda, Vaclav;
Vojackova, Eva;
Cerna, Katerina;
Didi, Jana;
Pytlik, Robert;
Prochazka, Vit;
Prouzova, Zuzana;
Zlamalikova, Lenka;
Pospisilova, Sarka;
Evans, Andrew;
Zent, Clive S;
Kren, Leos;
Trneny, Marek;
Mayer, Jiri;
Janikova, Andrea;
Mraz, Marek
The Role of Microrna-150 in the Prognosis and Transformation of Follicular Lymphoma
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- Medientyp: E-Artikel
- Titel: The Role of Microrna-150 in the Prognosis and Transformation of Follicular Lymphoma
- Beteiligte: Musilova, Katerina; Pavlasova, Gabriela; Seda, Vaclav; Vojackova, Eva; Cerna, Katerina; Didi, Jana; Pytlik, Robert; Prochazka, Vit; Prouzova, Zuzana; Zlamalikova, Lenka; Pospisilova, Sarka; Evans, Andrew; Zent, Clive S; Kren, Leos; Trneny, Marek; Mayer, Jiri; Janikova, Andrea; Mraz, Marek
- Erschienen: American Society of Hematology, 2016
- Erschienen in: Blood
- Sprache: Englisch
- DOI: 10.1182/blood.v128.22.4125.4125
- ISSN: 0006-4971; 1528-0020
- Schlagwörter: Cell Biology ; Hematology ; Immunology ; Biochemistry
- Entstehung:
- Anmerkungen:
- Beschreibung: <jats:title>Abstract</jats:title> <jats:p>We and others have shown that deregulation of microRNAs (miRNAs) is associated with the biology of B cell malignancies, including regulation of B cell proliferation and survival (Musilova & Mraz, Leukemia, 2015). We focused on studying miRNAs that associate with the aggressiveness of FL and its transformation to diffuse large B cell lymphoma (DLBCL).</jats:p> <jats:p>First, we analyzed the expression of 380 miRNAs (TaqMan Arrays, ABI) in 8 paired primary samples of FL that subsequently transformed to DLBCL. We identified statistically significant changes (P<0.05, fold change >1.8) in the expression of 5 miRNAs. The most significant change was the down-regulation of miR-150 (~5 fold, P=0.01). Similarly, we observed significantly reduced miR-150 levels in an independent cohort of non-paired samples of FL before vs. after transformation to DLBCL, and miR-150 was significantly less expressed in de novo DLBCL in comparison with FL. MicroRNA miR-150 is of particular interest as we have shown that its expression determines BCR signaling propensity in chronic lymphocytic leukemia (CLL) B cells, and low levels associated with worse survival (Mraz et al., Blood, 2014). Therefore, we analyzed miR-150 expression in a cohort of 89 FL samples. We noticed that miR-150 expression was lower in samples from patients with a FLIPI score ≥3 (P=0.03), and with high Ki67 positivity (>20%; P=0.003). Moreover, FL patients with low miR-150 levels (<median) had significantly shorter survival (median survival 6.2 years vs. not reached; P=0.007; HR 3.0 [CI: 1.3-6.8]).</jats:p> <jats:p>To determine the potential reason for variable miR-150 levels in FL B cells, we tested the effect of microenvironmental interactions on its expression. In this experiment, a short term (48hrs) co-culture of B cell lymphoma cells with stromal cells (HS-5) led to down-regulation of miR-150 levels (P<0.05). Next we investigated the functional role of miR-150 by silencing its newly identified target, namely GAB1, in lymphoma B cells. The transfection of siGAB1 resulted in a significant reduction of BCR signaling after anti-IgM treatment (10ug/ml, assessed by calcium influx). We further showed that GAB1 is an adaptor molecule that allows for higher activity of the PI3K/AKT signaling pathway.</jats:p> <jats:p>CONCLUSION: Low miR-150 levels associate with a shorter overall survival in FL. This could be used as a reasonable prognostic marker since high miRNA stability allows reliable analyses of miR-150 levels from formalin-fixed, paraffin-embedded (FFPE) samples. Interactions with stromal cells and/or soluble microenvironmental factors down-modulate miR-150 levels in B cells, which support their BCR signalling potential. We are further investigating to what extent the miR-150 down-regulation is causally connected with the aggressiveness and/or transformation of FL.</jats:p> <jats:p>This work was supported by: the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601); the European Union's Horizon 2020 research and innovation programme under grant agreement No. 692298; the research grant GACR (16-13334Y); the Ministry of Health of the Czech Republic, grant nr. 16-29622A. All rights reserved. This work was financed from the SoMoPro II Programme (project No. 4SGA8684), co-financed by European Union and the South-Moravian Region. This publication reflects only the author's views and the Union is not liable for any use that may be made of the information contained therein; Masaryk university as part of the project "New approaches in research, diagnostics and therapy of hematological malignancies III", number MUNI/A/1028/2015 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2016; the Ministry of Health of the Czech Republic - conceptual development of research organization (FNBr, 65269705, Sup 3/16); the Ministry of Education, Youth and Sports of the Czech Republic, grant nr. LD15144 (COST CZ); the research grant TACR (TEO2000058/2014-2019); and EHA Research Fellowship award granted by the European Hematology Association. G.P. is a city of Ostrava scholarship holder.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
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