Ikaros: the guardian of the immune system

In a scientific breakthrough that aids our understanding of the internal wiring of immune cells, researchers at Monash University in Australia have cracked the code behind Ikaros, a protein essential for cell development immune and protection against pathogens and cancer.

The results of discovery were published in Nature Immunology.

Ikaros: what is its reaction function?

This research, led by the eminent Professor Nicholas Huntington of Monash University's Biomedicine Discovery Institute, is poised to reshape our understanding of genetic control networks and their impact on everything from eye color to cancer susceptibility and the design of new therapies. The study promises fundamental insights into the mechanisms that protect us from infections and tumors.

When the transcription factor Ikaros/Ikzf1 was deliberately blocked, both in preclinical models and in humans, the once-potent activity of natural killer (NK) cells, the front-line warriors of our immune system, collapsed.

Loss of this transcription factor in NK cells resulted in widespread dysregulation of NK cell development and function, impeding their ability to recognize and kill virus-infected cells and clear metastatic tumor cells from the circulation.

Aiolos/Ikzf3 and Helios/Ikzf2, a related family member, were found to partially compensate for the loss of Ikaros, as when multiple IKZF family members were inhibited, NK cells underwent rapid death.

Mechanistically, Aiolos and Ikaros have been found to directly bind and activate most members of the JUN/FOS family, transcription factors known for their essential role in human embryonic development and tissue function.

This discovery opens the door to the prospect of potential new anticancer therapies. NK cells, our first line of defense against pathogens and internal threats such as tumors, could be strengthened by therapies that improve their ability to kill by targeting Ikaros and JUN/FOS biology.

Professor Huntington points out that drugs targeting Ikaros/Aiolos have already received approval from the US Food and Drug Administration (FDA) and the local Therapeutic Goods Administration (TGA) for the treatment of B-cell malignancies.

He noted: “But until now we haven't understood how these drugs work. Armed with this new information, it may be possible to develop new drugs targeting these complexes that could offer a differentiated pharmacology and therapeutic index for the treatment of diseases.”

Importantly, on this front, Professor Huntington's team was able to demonstrate that Ikaros has a conserved role in healthy B cells and therefore potentially in B cell tumors.