Ikaros family zinc finger protein 1 (IKZF1), Ikaros family zinc finger protein 3 (IKZF3) (IKZF1 (Ikaros), IKZF3 (Aiolos))

Ikaros family zinc finger protein 1 and 3—commonly referred to as IKZF1 (Ikaros) and IKZF3 (Aiolos)—are members of the Ikaros zinc finger group of transcription factors responsible for the regulation of hematopoietic stem cell differentiation, immune cell fate specification, and chromatin remodeling. Both proteins feature N-terminal zinc finger domains for DNA binding and C-terminal domains for protein-protein interactions, enabling combinatorial control of gene expression via formation of heterodimers and recruitment of chromatin modifying complexes. IKZF1 is crucial for early lymphoid progenitor emergence and B/T cell lineage commitment, while IKZF3 predominantly regulates late-stage lymphocyte development and T-cell functional modulation. Disease-associated alterations (mutations, deletions) in IKZF1 or IKZF3 disrupt normal immune cell development and contribute to the pathogenesis and therapy resistance of B-cell malignancies and multiple myeloma. Targeted protein degraders and immunomodulatory drugs leverage the vulnerability created by IKZF1/3 dependence in cancer cells, resulting in enhanced therapeutic efficacy but also necessitating careful biomarker-based patient selection.

Other names

IKZF1: IkarosIKZF3: AiolosBoth: Ikaros zinc finger transcription factor familyIkZF transcription factors

Immunomodulatory drugs (IMiDs, such as lenalidomide/pomalidomide) bind cereblon and promote ubiquitination/degradation of IKZF1/IKZF3, leading to anti-proliferative and pro-apoptotic effects in malignant cells.