Major breakthrough unveils immune system's guardian: IKAROS
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, an essential protein for immune cell development and protection against pathogens and cancer.
This disruptive research, led by Professor Nicholas Huntington of Monash University’s Biomedicine Discovery Institute, is poised to reshape our comprehension of gene control networks and its impact on everything from eye colour to cancer susceptibility and design of novel therapies.
The study, published in Nature Immunology, promises pivotal insights into the mechanisms safeguarding us against infections and cancers. When the transcription factor IKAROS/Ikzf1 was deliberately obstructed, the normal activity of Natural Killer (NK) cells, our immune system's frontline warriors, plummeted. Loss of this transcription factor in NK cells resulted in widespread dysregulation of NK cell development and function, preventing their ability to recognize and kill virus-infected cells and clear metastatic tumour cells from circulation. AIOLOS/Ikzf3 and Helios/Ikzf2, related protein family members, 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 were found to directly bind and activate most members of the JUN/FOS family, transcription factors known for their essential roles in human embryo development and tissue function.
This discovery opens the door to the prospect of potential novel cancer therapeutics. NK cells, our first line of defence against pathogens and internal threats like cancers, could be fortified by therapies enhancing their killing prowess by targeting IKAROS and JUN/FOS biology.
Professor Huntington notes that 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,” he said.
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.
“While drugs targeting IKZF1/3 are approved for B cell malignancies, directing these drugs to specific cell types in humans or crafting specialized drugs for these transcription factor families may necessitate another decade of rigorous drug and clinical development. If strategically and commercially viable, this could pave the way for a new era in medical advancements,” said Professor Huntington.
Read the full paper in Nature Immunology, titled IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development
DOI: 10.1038/s41590-023-01718-4
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.
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