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Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.
IKZF1 (chromosome 7p12.2) encodes Ikaros, a zinc-finger transcription regulator of haematopoietic differentiation and B- and T-lymphocyte development that binds gamma-satellite DNA, activates the CD3-delta enhancer, represses TDT during thymocyte differentiation, and regulates transcription through HDAC-dependent and independent complexes and the NuRD and BAF chromatin remodellers; dominant-negative isoforms modulate its function (UniProt Q13422). In OnCo it is the neosubstrate that thalidomide, lenalidomide and pomalidomide recruit to cereblon for ubiquitination and proteasomal degradation, and that golcadomide, a cereblon E3 ligase modulator, degrades alongside Aiolos; the loss lowers IRF4 and MYC in myeloma cells and stimulates T cells.
In plain words · Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.
Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.
Ikaros is degraded rather than inhibited: the immunomodulatory drugs bind cereblon in the CRL4 ubiquitin ligase and change its substrate preference so that Ikaros and Aiolos are ubiquitinated and destroyed (lenalidomide mechanism steps).
4 products aim at IKZF1 (Ikaros): 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 bone marrow cells and lymphoid tissue cells: HPA finds the gene group enriched in bone marrow, lymphoid tissue, and the 4 medicines aimed at it (Lenalidomide, Pomalidomide, Thalidomide and more) act on the wild-type protein, so the normal lineage is hit too. HPA IKZF1: RNA group enriched (bone marrow 160 nTPM, lymphoid tissue 99 nTPM); no normal tissue stained 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 1 specific cancer type at or above 0.5 (acute lymphoblastic leukemia). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas IKZF1 tissue; Human Protein Atlas IKZF1 pathology; Open Targets ENSG00000185811 associations
First described 1996. Earliest sequence paper UniProt cites for the protein: Nietfeld et al, Immunol. Lett, 1996, "Cloning and sequencing of hIk-1, a cDNA encoding a human homologue of mouse Ikaros/LyF-1". Source.
Ikaros is degraded rather than inhibited: the immunomodulatory drugs bind cereblon in the CRL4 ubiquitin ligase and change its substrate preference so that Ikaros and Aiolos are ubiquitinated and destroyed (lenalidomide mechanism steps). The lenalidomide record calls this the basis for CELMoDs and molecular-glue degraders generally.
RNA: group enriched (bone marrow 160 nTPM, lymphoid tissue 99 nTPM), detected in many normal tissues.
No normal tissue stained high; medium in Bone marrow, Lymph node, Placenta, Spleen, Tonsil.
No cancer stained high; medium in glioma, lymphoma.
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.
Thalidomide is the drug behind the 1960s birth-defect tragedy, rehabilitated as the first immunomodulatory myeloma drug and the parent of lenalidomide and pomalidomide.
Query for this target: (TITLE:"IKZF1" OR ABSTRACT:"IKZF1" OR TITLE:"Ikaros" OR ABSTRACT:"Ikaros" OR TITLE:"IKAROS" OR ABSTRACT:"IKAROS" OR TITLE:"ZNFN1A1" OR ABSTRACT:"ZNFN1A1" OR TITLE:"IKAROS family zinc finger 1" OR ABSTRACT:"IKAROS family zinc finger 1") 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 IKZF1 (Ikaros), not a curated reading list.
Shares Transcriptional machinery & addiction, MYC and the tag wave5-target.
Shares Diffuse large B-cell lymphoma and the tag wave5-target.
Shares Diffuse large B-cell lymphoma and the tag wave5-target.
Shares Diffuse large B-cell lymphoma and the tag wave5-target.
Shares Thalidomide, Molecular glue discovery platforms, Pomalidomide, Lenalidomide.
Shares Cereblon E3 ligase modulators (CELMoDs), Ubiquitin-proteasome system & protein homeostasis, Lenalidomide, Multiple myeloma.
Shares Cereblon E3 ligase modulators (CELMoDs), Lenalidomide, Multiple myeloma.
Shares Cereblon E3 ligase modulators (CELMoDs), Pomalidomide, Multiple myeloma.