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Aiolos is Ikaros' partner transcription factor in B cells and plasma cells. The myeloma drugs lenalidomide, pomalidomide and golcadomide destroy Aiolos and Ikaros together by rerouting them to the cell's protein-disposal system.
IKZF3 (chromosome 17q12-q21.1) encodes Aiolos, a transcription factor that regulates lymphocyte differentiation and is essential for B-cell differentiation, proliferation and maturation to an effector state; it regulates BCL2 expression and controls IL-2-dependent apoptosis in T cells (UniProt Q9UKT9). In OnCo it is the second cereblon neosubstrate, alongside Ikaros, that lenalidomide and pomalidomide recruit for ubiquitination and proteasomal degradation and that golcadomide degrades; the loss lowers IRF4 and MYC in myeloma cells and stimulates T and NK cells.
In plain words · Aiolos is Ikaros' partner transcription factor in B cells and plasma cells. The myeloma drugs lenalidomide, pomalidomide and golcadomide destroy Aiolos and Ikaros together by rerouting them to the cell's protein-disposal system.
Aiolos is Ikaros' partner transcription factor in B cells and plasma cells. The myeloma drugs lenalidomide, pomalidomide and golcadomide destroy Aiolos and Ikaros together by rerouting them to the cell's protein-disposal system.
Aiolos and Ikaros are destroyed by the same molecular-glue mechanism: the drug binds cereblon in the CRL4 ligase, the complex gains affinity for both transcription factors, and both are ubiquitinated (lenalidomide mechanism steps).
3 products aim at IKZF3 (Aiolos): degraders. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
Lineage antigen shared with normal T-cells: HPA finds the gene group enriched in that blood lineage, and the 3 medicines aimed at it (Lenalidomide, Pomalidomide, Golcadomide) act on the wild-type protein, so the normal lineage is hit too. HPA IKZF3: RNA group enriched (intestine 11 nTPM, lymphoid tissue 38 nTPM); blood lineage group enriched (B-cells 13 nTPM, T-cells 29 nTPM); high antibody staining in 7 normal tissues; highest cancer staining lymphoma (9 of 12 high). Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Multiple myeloma, Lymphoma); Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas IKZF3 tissue; Human Protein Atlas IKZF3 pathology; Open Targets ENSG00000161405 associations
First described 1999. Earliest sequence paper UniProt cites for the protein: Hosokawa et al, Genomics, 1999, "Human aiolos, an ikaros-related zinc finger DNA binding protein: cDNA cloning, tissue expression pattern, and chromosomal mapping". Source.
Aiolos and Ikaros are destroyed by the same molecular-glue mechanism: the drug binds cereblon in the CRL4 ligase, the complex gains affinity for both transcription factors, and both are ubiquitinated (lenalidomide mechanism steps). Pomalidomide keeps this activity after lenalidomide failure.
RNA: group enriched (intestine 11 nTPM, lymphoid tissue 38 nTPM), detected in many normal tissues. Blood: group enriched (B-cells 13 nTPM, T-cells 29 nTPM).
Medium: Bone marrow.
Medium only: glioma.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
Golcadomide is a next-generation lenalidomide-like pill that degrades two lymphoma transcription factors far more potently, now in phase 3 with R-CHOP.
Lenalidomide is a thalidomide descendant that glues the proteins IKZF1 and IKZF3 to cereblon so the cell destroys them, killing plasma cells and rousing T cells. It is the backbone of myeloma treatment and maintenance, also used in mantle cell and follicular lymphoma, and generic since 2022.
The third-generation thalidomide analogue for myeloma that has failed lenalidomide, and since 2020 the first new drug for Kaposi sarcoma in two decades.
Query for this target: (TITLE:"IKZF3" OR ABSTRACT:"IKZF3" OR TITLE:"Aiolos" OR ABSTRACT:"Aiolos" OR TITLE:"ZNFN1A3" OR ABSTRACT:"ZNFN1A3" OR TITLE:"IKAROS family zinc finger 3" OR ABSTRACT:"IKAROS family zinc finger 3") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about IKZF3 (Aiolos), not a curated reading list.
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Shares Cereblon E3 ligase modulators (CELMoDs), Ubiquitin-proteasome system & protein homeostasis, Lenalidomide, Relapsed or refractory multiple myeloma.
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