TY  - JOUR
A1  - Paczkowska, Julia
A1  - Janiszewska, Joanna
A1  - Ustaszewski, Adam
A1  - Bein, Julia
A1  - Skalski, Marcin
A1  - Dzikiewicz-Krawczyk, Agnieszka
A1  - Rozwadowska, Natalia
A1  - Hansmann, Martin-Leo
A1  - Hartmann, Sylvia
A1  - Giefing, Maciej
T1  - Deregulated miRNAs contribute to silencing of B-cell specific transcription factors and activation of NF-κB in classical Hodgkin lymphoma
T2  - Cancers
N2  - Simple Summary: The role of transcriptionally deregulated miRNAs (microRNAs) in classical Hodgkin lymphoma (cHL) is still not fully understood. To address this issue, we have performed global miRNA expression profiling of commonly used cHL cell lines and we present a complete cHL miRNome (microRNome). Within this group, we identify miRNAs recurrently deregulated in cHL cell lines, and compare them to non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells. Moreover, we show that several of the recurrently overexpressed miRNAs in cHL cell lines, and also primary microdissected HRS (Hodgkin and Reed-Sternberg) cells, target known B-cell-related transcription factors and NF-κB inhibitors. These findings provide evidence that deregulated miRNAs contribute to the loss of B-cell phenotype and NF-κB activation observed in this lymphoma.
Abstract: A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.
KW  - classical Hodgkin lymphoma
KW  - microdissection
KW  - miRNA
KW  - loss of B-cell phenotype
KW  - NF-κB
KW  - B-cell transcription factors
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62171
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-621716
SN  - 2072-6694
N1  - This research was funded by the Polish National Science Center through the 2014/14/M/ NZ2/00529 grant to MG and the 2019/32/T/NZ5/00441 Etiuda scholarship to JP. SH is supported by the German Research Foundation (DFG, HA6145/3-1). MG, ADz-K and NR received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 952304.
VL  - 13
IS  - 13, art. 3131
SP  - 1
EP  - 15
PB  - MDPI
CY  - Basel
ER  -