Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3) (IKZF1/3)

IKZF1 (Ikaros) and IKZF3 (Aiolos) are C2H2-type zinc finger transcription factors that serve as master regulators of hematopoietic development and lymphocyte differentiation (UniProt Q13422, Q9UKT9). They function by binding to specific DNA motifs and recruiting chromatin-remodeling complexes to modulate the expression of genes essential for B-cell and T-cell maturation (Kronke et al., 2014, Science). In hematologic malignancies like multiple myeloma, these proteins are vital for cell survival as they maintain the expression of the oncogenic transcription factor IRF4 (Lu et al., 2014, Science). These factors are the primary therapeutic targets of immunomodulatory imide drugs (IMiDs), including lenalidomide and pomalidomide, which act as molecular glues (Chamberlain et al., 2014, Nature Structural & Molecular Biology). These drugs facilitate a neomorphic interaction between the Cereblon (CRBN) E3 ubiquitin ligase and the IKZF1/3 proteins, leading to their rapid polyubiquitination and proteasomal degradation (Matyskiela et al., 2016, Nature). The resulting depletion of IKZF1 and IKZF3 triggers apoptosis in malignant B cells and enhances T-cell mediated immune responses, providing a dual mechanism of action (Gandhi et al., 2014, British Journal of Haematology).

Other names

IkarosAiolosZNFN1A1ZNFN1A3Zinc finger protein, subfamily 1A, 1Zinc finger protein, subfamily 1A, 3LYF1hIK-1

Drugs targeting these proteins function as molecular glues that bridge the interaction between the Cereblon (CRBN) E3 ubiquitin ligase complex and the IKZF1/3 transcription factors (Kronke et al., 2014, Science). This recruitment leads to the site-specific polyubiquitination of IKZF1 and IKZF3, marking them for rapid degradation by the 26S proteasome (Lu et al., 2014, Science). The loss of these factors downregulates downstream targets like IRF4 and MYC, leading to cell cycle arrest in myeloma cells while simultaneously derepressing interleukin-2 (IL-2) production in T cells (Gandhi et al., 2014, British Journal of Haematology).