Ikaros family zinc finger protein (IKZF)

The Ikaros family zinc finger (IKZF) proteins are a group of five transcription factors (IKZF1-5) that play critical roles in the regulation of hematopoiesis and lymphocyte development (UniProt: Q13422). These proteins, characterized by highly conserved N-terminal zinc finger DNA-binding domains and C-terminal dimerization domains, function as both transcriptional activators and repressors by interacting with chromatin remodeling complexes such as NuRD (PubMed: 24284190). In clinical oncology, IKZF1 (Ikaros) and IKZF3 (Aiolos) are of particular importance as they are the primary neo-substrate targets of immunomodulatory imide drugs (IMiDs) and cereblon E3 ligase modulators (CELMoDs) (PubMed: 24284191). These therapeutic agents act as molecular glues, facilitating the recruitment of IKZF1/3 to the CRL4-CRBN E3 ubiquitin ligase complex, which leads to their polyubiquitination and subsequent proteasomal degradation (NIH: PMC4053807). This degradation is lethal to multiple myeloma cells, which are dependent on these factors for survival, while simultaneously enhancing T-cell and natural killer cell activity, making the IKZF family a central axis in modern immunotherapy for hematologic malignancies (PubMed: 29158374).

Other names

Ikaros familyIKZF familyZinc finger protein IkarosAiolos (IKZF3)Helios (IKZF2)Eos (IKZF4)Pegasus (IKZF5)

Molecular glue-induced targeted protein degradation via the CRL4-CRBN E3 ubiquitin ligase complex (PubMed: 24284190).