Cover Image

Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor pro...

Full description

Saved in:
Bibliographic Details
Main Authors: Giménez, Neus (Author) , Schulz, Ralph (Author) , Higashi, Morihiro (Author) , Aymerich, Marta (Author) , Villamor, Neus (Author) , Delgado, Julio (Author) , Juan, Manel (Author) , López-Guerra, Mònica (Author) , Campo, Elias (Author) , Rosich, Laia (Author) , Seiffert, Martina (Author) , Colomer, Dolors (Author)
Format: Article (Journal)
Language:English
Published: [2020]
In: Leukemia
Year: 2019, Volume: 34, Issue: 1, Pages: 100-114
ISSN:1476-5551
DOI:10.1038/s41375-019-0507-8
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41375-019-0507-8
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41375-019-0507-8
Get full text
Author Notes:Neus Giménez, Ralph Schulz, Morihiro Higashi, Marta Aymerich, Neus Villamor, Julio Delgado, Manel Juan, Mònica López-Guerra, Elias Campo, Laia Rosich, Martina Seiffert, Dolors Colomer
Description
Summary:Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and -unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.
Item Description:Published online: 13 June 2019
Gesehen am 21.04.2020
Physical Description:Online Resource
ISSN:1476-5551
DOI:10.1038/s41375-019-0507-8

Similar Items