The dynamic functions of IRF4 in B cell malignancies

Abstract

The trajectory of B cell development goes through subsequent steps governed by complex genetic programs, strictly regulated by multiple transcription factors. Interferon regulatory factor 4 (IRF4) regulates key points from pre-B cell development and receptor editing to germinal center formation, class-switch recombination and plasma cell differentiation. The pleiotropic ability of IRF4 is mediated by its “kinetic control”, allowing different IRF4 expression levels to activate distinct genetic programs due to modulation of IRF4 DNA-binding affinity. IRF4 is implicated in B cell malignancies, acting both as tumor suppressor and as tumor oncogene in different types of precursors and mature B cell neoplasia. Here, we summarize the complexity of IRF4 functions related to different DNA-binding affinity, multiple IRF4-specific target DNA motif, and interactions with transcriptional partners. Moreover, we describe the unique role of IRF4 in acute leukemias and B cell mature neoplasia, focusing on pathogenetic implications and possible therapeutic strategies in multiple myeloma and chronic lymphocytic leukemia.

SARS‐CoV‐2 infection is not associated with the emergence of monoclonal gammopathies

“…Several studies support the theory that autoimmune, infectious, and inflammatory diseases release immune‐related factors stimulating an antigenic response possibly resulting in the production of monoclonal immunoglobulins 10–12 . In line with this, chronic antigen stimulation is a predisposing factor for the onset of MGUS and other B‐cell disorders 13–17 . Indeed, infections could trigger plasma cell‐transported IgH translocations (crucial for clonal proliferation), which are found in almost 50% of patients with MGUS 18 .…”

“…[10][11][12] In line with this, chronic antigen stimulation is a predisposing factor for the onset of MGUS and other B-cell disorders. [13][14][15][16][17] Indeed, infections could trigger plasma cell-transported IgH translocations (crucial for clonal proliferation), which are found in almost 50% of patients with MGUS. 18 For this reason, SPEP in patients with MC during a period of active infection requires monitoring to ascertain whether the observed MC is temporary.…”

Genetic landscape and prognostic value of IRF4 alterations in Diffuse large B-cell lymphoma patients

“…Activating mutations or translocations in MM similarly result in MUM1 overexpression (Heintel et al, 2008). Which result in abnormal antigen receptor signaling activation(Ikeda and Tagawa, 2021; Maffei et al, 2022). IRF4 mRNA expression is con rmed to be an independent risk factor for poor survival (Heintel et al, 2008).…”

Reclassification of diffuse large B cell lymphoma to large B cell lymphoma with IRF4 rearrangement in an adult population

“…1 IRF4 is a member of the interferon regulatory factor (IRF) family of transcription factors which plays an essential role in multiple stage of B cell development, including early B cell development, germinal centre formation and plasma cell differentiation. 2 Although reports on LBCL-IRF4 are limited, it is estimated to be rare. 3 Clinically, it typically presents in children and young adults with limited stage disease and there seems to be a predisposition for the head and neck lymph nodes and Waldeyer's ring.…”

“…Large B cell lymphoma with IRF4 rearrangement (LBCL‐IRF4) is a newly recognised entity in the 2017 update of the 4th World Health Organisation (WHO) classification of tumours of haematopoietic and lymphoid tissues which has been retained in the 5th edition 1 . IRF4 is a member of the interferon regulatory factor (IRF) family of transcription factors which plays an essential role in multiple stage of B cell development, including early B cell development, germinal centre formation and plasma cell differentiation 2 . Although reports on LBCL‐IRF4 are limited, it is estimated to be rare 3 …”