Ikaros transcription factors are essential for adaptive lymphocyte function. Yet, their role in innate lymphopoiesis is unknown. Using conditional genetic inactivation, a new study advances our understanding of the internal wiring of immune cells.
In a scientific breakthrough, researchers at Monash University in Australia have cracked the code behind IKAROS, an essential protein for immune cell development and protection against pathogens and cancer.
This study is set to revolutionize our understanding of gene control networks, impacting areas such as eye color, cancer susceptibility, and the development of novel therapies. By inhibiting the transcription factor Ikaros/Ikzf1, the activity of Natural Killer (NK) cells, crucial immune system components, significantly decreased.
Blocking this transcription factor led to disruptions in NK cell development and function, hindering their capacity to identify and eliminate virus-infected cells, as well as clear metastatic tumor cells from circulation.
Aiolos/Ikzf3 and Helios/Ikzf2, related family members, were identified as partial compensators for losing Ikaros. When multiple IKZF-family members were inhibited, NK cells experienced rapid death. Mechanistically, Aiolos and Ikaros were found to bind and activate most JUN/FOS family members directly, transcription factors crucial for human embryo development and tissue function.
This discovery suggests the potential for novel cancer therapeutics. Enhancing the killing ability of NK cells, our first line of defense against pathogens and internal threats like cancers could be achieved by targeting IKAROS and JUN/FOS biology.
Professor Nicholas Huntington of Monash University’s Biomedicine Discovery Institute said, “Drugs targeting IKAROS/AIOLOS have already received approval from the US Food and Drug Administration (FDA) and local Therapeutic Goods Administration (TGA) for the treatment of B cell malignancy but until now we haven’t understood how these drugs work, armed with this new information it could be possible to develop novel drugs targeting these complexes which may offer differentiated pharmacology and therapeutic index for treating disease.”
“Importantly on this front, Professor Huntington’s team were able to show that IKAROS had a conserved role in healthy B cells and thus potentially B cell cancers.”
Journal Reference:
- Goh, W., Sudholz, H., Foroutan, M. et al. IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development. Nat Immunol (2024). DOI: 10.1038/s41590-023-01718-4