Related Experiment Video

Updated: Nov 16, 2025

Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization
08:57

Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization

Published on: October 6, 2019

10.4K

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

Rossana Maffei1,2, Stefania Fiorcari3, Stefania Benatti3

  • 1Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy. rossana.maffei@unimore.it.

Leukemia
|February 24, 2021
PubMed

Insights

Interferon regulatory factor 4 (IRF4) dampens B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL). Lowering IRF4 enhances BCR signaling, impacting key proteins like SYK and IKAROS, offering therapeutic insights.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Interferon regulatory factor 4 (IRF4) is a key regulator in immune development and function.
  • B-cell receptor (BCR) signaling plays a critical role in chronic lymphocytic leukemia (CLL) pathogenesis.

Purpose of the Study:

  • To investigate the role of IRF4 in modulating BCR signaling responsiveness in CLL cells.
  • To elucidate the molecular mechanisms by which IRF4 influences BCR signaling pathways.

Main Methods:

  • IRF4 levels were modulated in CLL cells using transfection and small-interfering RNAs.
  • Protein levels of spleen tyrosine kinase (SYK) and IKAROS were assessed.
  • Pharmacological treatments including lenalidomide, avadomide (IMIDs), and ibrutinib were utilized.

Main Results:

  • Elevated IRF4 levels attenuated BCR signaling, reducing AKT, ERK phosphorylation, and calcium release.
  • IRF4 reduction enhanced BCR signaling strength, correlating with increased SYK and IKAROS.
  • IRF4 negatively regulates SYK and IKAROS expression; IKAROS promotes BCR signaling by downregulating SHIP1.
  • IMIDs increased IRF4, decreased IKAROS, and impaired BCR-mediated survival, even with ibrutinib.

Conclusions:

  • IRF4 acts as a negative regulator of BCR signaling in CLL.
  • Low IRF4 levels facilitate efficient BCR signal transmission via SYK and IKAROS accumulation.
  • Targeting IRF4 and IKAROS pathways, potentially with IMIDs and ibrutinib, may offer therapeutic strategies for CLL.

More Related Videos

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF311:44

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3

Published on: January 24, 2016

12.2K
Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice08:09

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice

Published on: March 24, 2017

8.3K

Related Concept Videos

NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
8.6K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.8K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.5K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
10.2K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.1K
T Cell Types and Functions01:24

T Cell Types and Functions

When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
1.7K