Program DHC-Virtual
20 - 21 January 2021
Abstracts Lymphoid session 3
IRF8 is a transcriptional regulator of CD37 in DLBCL
21 January
08:54 09:06
A. van Spriel

IRF8 is a transcriptional regulator of CD37 expression in diffuse large B-cell lymphoma

Suraya Elfrink (1), Luuk Janssen (2), Angelique Kenyon (1), Raymond Steen (1), Daynelys de Windt (1), Martin ter Beest (1), Marijke Baltissen (3), Pascal Jansen (3), Michiel Vermeulen (3), Michiel van den Brand (2,4), Blanca Scheijen (2), Annemiek van Spriel (1)
(1) Radboudumc, Tumor immunology, Nijmegen, (2) Radboudumc, Pathology, Nijmegen, (3) Radboud Institute for Molecular Life Sciences, Molecular biology, Nijmegen, (4) Rijnstate Hospital, Pathology-DNA, Arnhem
No potential conflicts of interest

Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma that is still incurable in a large fraction of patients. Transmembrane protein CD37 is highly expressed on mature B lymphocytes, but loss of CD37 expression is observed in ~ 50% of DLBCL patients which correlates with inferior treatment outcome. However, the underlying molecular mechanisms that control CD37 expression in malignant B cells are still unknown. 


Here we investigated regulation of the CD37 gene in human DLBCL at the (epi-)genetic and transcriptional level. 


No differences were observed in DNA methylation patterns and single nucleotide variants within the promoter region of the CD37 gene between CD37-positive and CD37-negative DLBCL samples. On the contrary, CD37-negative DLBCL cell lines lacked CD37 promoter activity in transient reporter assays, suggesting differential transcription regulation between CD37-negative and CD37-positive DLBCL. Using an unbiased SILAC-based quantitative proteomic approach, we detected significantly higher expression levels of transcription factor IRF8 in nuclear extracts of CD37-positive as compared to CD37-negative DLBCL. Direct binding of IRF8 to the promoter region of CD37 was confirmed by DNA pull-down combined with mass spectrometry and targeted chromatin immunoprecipitation. Functional analysis showed that overexpression of IRF8 enhanced CD37 protein expression, while CRISPR/Cas9 knockout of IRF8 decreased CD37 levels in DLBCL cell lines. Immunohistochemical analysis in a large cohort of primary DLBCL (n=206) revealed significant more loss of IRF8 in CD37-negative versus CD37-positive DLBCL.


Together, this study provides new insight into the molecular mechanism underlying differential CD37 expression, and reveals IRF8 as key transcriptional regulator of CD37 in human DLBCL.