Abstract
Ikaros is a zinc finger transcription factor (TF) of the Krüppel family member, which significantly regulates normal lymphopoiesis and tumorigenesis. Ikaros can directly initiate or suppress tumor suppressors or oncogenes, consequently regulating the survival and proliferation of cancer cells. Over recent decades, a series of studies have been devoted to exploring and clarifying the relationship between Ikaros and associated tumors. Therapeutic strategies targeting Ikaros have shown promising therapeutic effects in both pre-clinical and clinical trials. Nevertheless, the increasingly prominent problem of drug resistance targeted to Ikaros and its analog is gradually appearing in our field of vision. This article reviews the role of Ikaros in tumorigenesis, the mechanism of drug resistance, the progress of targeting Ikaros in both pre-clinical and clinical trials, and the potential use of associated therapy in cancer therapy.
Highlights
Ikaros is a zinc finger transcription factor (TF) and a member of the Krüppel family, which is called the IKAROS family zinc finger protein family (IKZF) and consists of other TFs named Ikaros, Helios, Aiolos, Eos, and Pegasus
Ikaros is affected by several interferon regulatory factors (IRFs), among which IRF4 and IRF8 were considered to induce the expression of Ikaros and its homologous gene Aiolos (Ma et al, 2008); another study showed that IRF8 rather than IRF4 triggers the IKZF1 promoter, and IRF5 could inhibit this activation (Fang et al, 2012)
Patients with newly diagnosed MM (NDMM) who were unsuitable for stem cell transplantation are associated with a considerable benefit in progression-free survival (PFS) [lenalidomide-dexamethasone vs. melphalan-prednisone-thalidomide (MPT); HR, 0.72; p < 0.001] and overall survival (OS) at the interim analysis and less frequent grade 3 or 4 toxic and adverse events (70 vs. 78%), with continuous lenalidomidedexamethasone intervention until disease progression compared with MPT (NCT00689936) (Benboubker et al, 2014)
Summary
Ikaros is a zinc finger transcription factor (TF) and a member of the Krüppel family, which is called the IKAROS family zinc finger protein family (IKZF) and consists of other TFs named Ikaros, Helios, Aiolos, Eos, and Pegasus. Ikaros is encoded by the IKZF1 gene (Zhao et al, 2020), exerting an essential effect on regulating normal lymphopoiesis and functions as a tumor suppressor (Winandy et al, 1995; Sigvardsson, 2018). It covers four zinc fingers at the N-terminal for binding to DNA by directly combining with the GGGAA core motif in vitro and at the A/GGAAA core motif in vivo. The mutations in IKZF are associated with recurrent infections, cytopenia (neutropenia, immune thrombocytopenia, and autoimmune hemolytic anemia), autoimmune diseases, and hematological malignancies (Kuehn et al, 2020). Germline mutation in IKZF1 has been reported to be associated with congenital pancytopenia (Goldman et al, 2012)
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