IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK

• Published in: Leukemia Vol. 35; no. 5; pp. 1330 - 1343
• Main Authors: Maffei, Rossana, Fiorcari, Stefania, Benatti, Stefania, Atene, Claudio Giacinto, Martinelli, Silvia, Zucchini, Patrizia, Potenza, Leonardo, Luppi, Mario, Marasca, Roberto
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2021; Nature Publishing Group
• Subjects: 13/109; 13/44; 13/89; 14/34; 631/67/1990/283/1895; 631/80/86; 82/29; 82/80; 96/2; 96/95; AKT protein; Antineoplastic Agents - pharmacology; B cells; B-cell receptor; Calcium; Cancer Research; Cell activation; Cell Line; Cell Line, Tumor; Chronic lymphocytic leukemia; Critical Care Medicine; Deoxyribonucleic acid; Development and progression; DNA; DNA-binding protein; Down-Regulation - genetics; Extracellular signal-regulated kinase; Genetic aspects; Health aspects; Hematology; Humans; Ikaros protein; Ikaros Transcription Factor - genetics; Immune system; Inositol; Inositol-1,4,5-trisphosphate 5-phosphatase; Intensive; Interferon; Interferon regulatory factor; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; Internal Medicine; Kinases; Lenalidomide - pharmacology; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukocytes, Mononuclear - drug effects; Lymphatic leukemia; Lymphocytes B; Medicine; Medicine & Public Health; Membrane proteins; Oncology; Phosphorylation; Physiological aspects; Protein-tyrosine kinase; Proteins; Receptors, Antigen, B-Cell; Signal Transduction - genetics; Signaling; Spleen; Spleen - drug effects; Syk Kinase - genetics; Syk protein; Transcription; Transcription factors; Tyrosine; Zinc finger proteins; Italy
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01178-5

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator of immune system development and function. Here, we investigated the role of IRF4 in controlling responsiveness to B-cell receptor (BCR) stimulation in chronic lymphocytic leukemia (CLL). We modulated IRF4 levels by transfecting CLL cells with an IRF4 vector or by silencing using small-interfering RNAs. Higher IRF4 levels attenuated BCR signaling by reducing AKT and ERK phosphorylation and calcium release. Conversely, IRF4 reduction improved the strength of the intracellular cascade activated by BCR engagement. Our results also indicated that IRF4 negatively regulates the expression of the spleen tyrosine kinase SYK, a crucial protein for propagation of BCR signaling, and the zinc finger DNA-binding protein IKAROS. We modulated IKAROS protein levels both by genetic manipulation and pharmacologically by treating CLL cells with lenalidomide and avadomide (IMIDs). IKAROS promoted BCR signaling by reducing the expression of inositol 5-phosphatase SHIP1. Lastly, IMIDs induced IRF4 expression, while down-regulating IKAROS and interfered with survival advantage mediated by BCR triggering, also in combination with ibrutinib. Overall, our findings elucidate the mechanism by which IRF4 tunes BCR signaling in CLL cells. Low IRF4 levels allow an efficient transmission of BCR signal throughout the accumulation of SYK and IKAROS.