IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
12 04 2022
12 04 2022
Historique:
received:
25
01
2021
accepted:
20
01
2022
pubmed:
28
1
2022
medline:
7
4
2022
entrez:
27
1
2022
Statut:
ppublish
Résumé
Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma (NHL) that is still incurable in a large fraction of patients. Tetraspanin CD37 is highly expressed on mature B lymphocytes, and multiple CD37-targeting therapies are under clinical development for NHL. However, CD37 expression is nondetectable in ∼50% of DLBCL patients, which correlates with inferior treatment outcome, but the underlying mechanisms for differential CD37 expression in DLBCL are still unknown. Here, we investigated the regulation of the CD37 gene in human DLBCL at the (epi-)genetic and transcriptional level. No differences were observed in DNA methylation within the CD37 promoter region between CD37-positive and CD37-negative primary DLBCL patient samples. On the contrary, CD37-negative DLBCL cells specifically lacked CD37 promoter activity, suggesting differential regulation of CD37 gene expression. Using an unbiased quantitative proteomic approach, we identified transcription factor IRF8 to be significantly higher expressed in nuclear extracts of CD37-positive as compared with CD37-negative DLBCL. Direct binding of IRF8 to the CD37 promoter region was confirmed by DNA pulldown assay combined with mass spectrometry and targeted chromatin immunoprecipitation (ChIP). Functional analysis indicated that IRF8 overexpression 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 a significant correlation of IRF8 expression with detectable CD37 levels. Together, this study provides new insight into the molecular mechanisms underlying differential CD37 expression in human DLBCL and reveals IRF8 as a transcriptional regulator of CD37 in B-cell lymphoma.
Identifiants
pubmed: 35086136
pii: 483731
doi: 10.1182/bloodadvances.2021004366
pmc: PMC9006271
doi:
Substances chimiques
Antigens, Neoplasm
0
CD37 protein, human
0
Interferon Regulatory Factors
0
Tetraspanins
0
interferon regulatory factor-8
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2254-2266Informations de copyright
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Références
PLoS One. 2015 Mar 26;10(3):e0122342
pubmed: 25811854
Histochem Cell Biol. 2015 Aug;144(2):133-46
pubmed: 25952155
N Engl J Med. 2018 Apr 12;378(15):1396-1407
pubmed: 29641966
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
J Cancer. 2015 Aug 07;6(10):953-61
pubmed: 26316891
J Immunol. 2005 Mar 1;174(5):2573-81
pubmed: 15728463
Nat Med. 2018 May;24(5):679-690
pubmed: 29713087
Proteomics. 2005 May;5(7):1742-5
pubmed: 15761957
Blood. 2014 Mar 13;123(11):1699-708
pubmed: 24385541
Cancer Cell. 2012 May 15;21(5):694-708
pubmed: 22624718
Elife. 2014 Jul 01;3:e02637
pubmed: 24986859
PLoS One. 2011;6(11):e27384
pubmed: 22096565
Expert Opin Investig Drugs. 2018 Feb;27(2):171-177
pubmed: 29323537
Biotechnol Lett. 2018 Dec;40(11-12):1459-1466
pubmed: 30293139
Trends Cancer. 2017 Jun;3(6):442-453
pubmed: 28718418
Nucleic Acids Res. 2013 Jan 7;41(1):e28
pubmed: 23066101
Oncotarget. 2014 Jul 15;5(13):5065-75
pubmed: 24970810
Br J Haematol. 2019 Apr;185(1):79-88
pubmed: 30681722
Leukemia. 2005 Aug;19(8):1376-83
pubmed: 15931266
Blood. 2016 Dec 29;128(26):3083-3100
pubmed: 27760757
Clin Cancer Res. 2008 May 15;14(10):2918-26
pubmed: 18483358
Trends Cell Biol. 2021 Feb;31(2):119-129
pubmed: 33248874
Cell. 1993 Oct 8;75(1):83-97
pubmed: 8402903
Proc Natl Acad Sci U S A. 2019 May 7;116(19):9511-9520
pubmed: 31000603
Leuk Lymphoma. 2014 Jan;55(1):136-42
pubmed: 23573829
Proteomics. 2016 Feb;16(3):417-26
pubmed: 26553150
Blood. 2019 Sep 19;134(12):946-950
pubmed: 31366619
Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245
pubmed: 29762716
Blood. 2018 Sep 6;132(10):999-1006
pubmed: 30037886
Nat Protoc. 2007;2(8):1896-906
pubmed: 17703201
Oncoimmunology. 2018 Jan 25;7(5):e1423183
pubmed: 29721381
Eur J Biochem. 1993 Jan 15;211(1-2):7-18
pubmed: 8425553
Cell. 2017 Oct 5;171(2):481-494.e15
pubmed: 28985567
Blood. 2018 May 3;131(18):2060-2064
pubmed: 29475959
Blood. 2013 Aug 1;122(5):726-33
pubmed: 23775715
Annu Rev Immunol. 2008;26:535-84
pubmed: 18303999
Carcinogenesis. 2006 Feb;27(2):197-204
pubmed: 16113057
J Immunol. 2006 Dec 1;177(11):7898-904
pubmed: 17114461
Curr Hematol Malig Rep. 2019 Oct;14(5):426-438
pubmed: 31559580
J Immunol. 2002 Jun 15;168(12):6224-31
pubmed: 12055236
Blood Res. 2015 Mar;50(1):26-32
pubmed: 25830127
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
J Exp Med. 2006 Jan 23;203(1):63-72
pubmed: 16380510
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Cancer Genet. 2020 Jul;245:6-16
pubmed: 32535543
J Clin Invest. 2016 Feb;126(2):653-66
pubmed: 26784544
Nat Methods. 2016 Sep;13(9):731-40
pubmed: 27348712
Best Pract Res Clin Haematol. 2018 Sep;31(3):209-216
pubmed: 30213390
Science. 2013 Feb 15;339(6121):819-23
pubmed: 23287718
Exp Hematol. 2008 Dec;36(12):1673-1681
pubmed: 18922617
Proc Natl Acad Sci U S A. 1994 May 24;91(11):5046-50
pubmed: 8197182
Blood. 2010 Aug 19;116(7):1025-34
pubmed: 20427703
Nat Rev Cancer. 2014 Jan;14(1):49-60
pubmed: 24505619
Crit Rev Oncol Hematol. 2013 Aug;87(2):146-71
pubmed: 23375551