DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1gene. Ikaros displays crucial functions in the hematopoietic system and its loss of function has been linked to the development of lymphoid leukemia. In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia. IKZF1 is upregulated in granulocytes, B cells, CD4 and CD8 T cells, and NK cells, and downregulated in erythroblasts, megakaryocytes and monocytes. In Ikaros knockout mice, T cells but not B cells are generated late in mouse development due to late compensatory expression of the related gene Aiolos (IKZF3). Ikaros point mutant mice are embryonic lethal due to anemia; they have severe defects in terminal erythrocyte and granulocyte differentiation, and excessive macrophage formation. SNPs located near the 3' region of IKZF1 in humans have been linked to susceptibility to childhood acute lymphoblastic leukemia (ALL) as well as type 1 diabetes. The two effects appear to be in opposite directions, with the allele marking susceptibility to ALL protecting from T1D and vice versa.
^Georgopoulos K, Moore DD, Derfler B (December 1992). "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment". Science258 (5083): 808–12. doi:10.1126/science.1439790. PMID1439790.
^Papathanasiou P, Perkins AC, Cobb BS, Ferrini R, Sridharan R, Hoyne GF, Nelms KA, Smale ST, Goodnow CC. (July 2003). "Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor". Immunity19 (1): 131–44. doi:10.1016/s1074-7613(03)00168-7.
^Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS. (September 2009). "Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia.". Ann Rev Immunol.41 (9): 1006–10. doi:10.1038/ng.430. PMID19684604.
^Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, Morgan BA. (April 1998). "Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors". Curr Biol8 (9): 508–915. doi:10.1016/S0960-9822(98)70202-7. PMID9560339.
^Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K. (March 1999). "Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes.". Immunity10 (3): 345–55. doi:10.1016/S1074-7613(00)80034-5. PMID10204490.
^Honma, Y; Kiyosawa H; Mori T; Oguri A; Nikaido T; Kanazawa K; Tojo M; Takeda J; Tanno Y; Yokoya S; Kawabata I; Ikeda H; Wanaka A (March 1999). "Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system". FEBS Lett. (NETHERLANDS) 447 (1): 76–80. doi:10.1016/S0014-5793(99)00265-3. ISSN0014-5793. PMID10218586.
^Perdomo, J; Holmes M; Chong B; Crossley M (December 2000). "Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities". J. Biol. Chem. (UNITED STATES) 275 (49): 38347–54. doi:10.1074/jbc.M005457200. ISSN0021-9258. PMID10978333.
^Koipally, Joseph; Georgopoulos Katia (June 2002). "Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression". J. Biol. Chem. (United States) 277 (26): 23143–9. doi:10.1074/jbc.M202079200. ISSN0021-9258. PMID11959865.
^Koipally, J; Georgopoulos K (June 2000). "Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity". J. Biol. Chem. (UNITED STATES) 275 (26): 19594–602. doi:10.1074/jbc.M000254200. ISSN0021-9258. PMID10766745.
Molnár A, Wu P, Largespada DA, et al. (1996). "The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse". J. Immunol.156 (2): 585–92. PMID8543809.
Kelley CM, Ikeda T, Koipally J, et al. (1998). "Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors". Curr. Biol.8 (9): 508–15. doi:10.1016/S0960-9822(98)70202-7. PMID9560339.
Honma Y, Kiyosawa H, Mori T, et al. (1999). "Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system". FEBS Lett.447 (1): 76–80. doi:10.1016/S0014-5793(99)00265-3. PMID10218586.
Sun L, Goodman PA, Wood CM, et al. (2000). "Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia". J. Clin. Oncol.17 (12): 3753–66. PMID10577847.
Hosokawa Y, Maeda Y, Ichinohasama R, et al. (2000). "The Ikaros gene, a central regulator of lymphoid differentiation, fuses to the BCL6 gene as a result of t(3;7)(q27;p12) translocation in a patient with diffuse large B-cell lymphoma". Blood95 (8): 2719–21. PMID10753856.
Koipally J, Georgopoulos K (2000). "Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity". J. Biol. Chem.275 (26): 19594–602. doi:10.1074/jbc.M000254200. PMID10766745.
Perdomo J, Holmes M, Chong B, Crossley M (2001). "Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities". J. Biol. Chem.275 (49): 38347–54. doi:10.1074/jbc.M005457200. PMID10978333.
Payne KJ, Nicolas JH, Zhu JY, et al. (2001). "Cutting edge: predominant expression of a novel Ikaros isoform in normal human hemopoiesis". J. Immunol.167 (4): 1867–70. doi:10.4049/jimmunol.167.4.1867. PMID11489963.
Koipally J, Heller EJ, Seavitt JR, Georgopoulos K (2002). "Unconventional potentiation of gene expression by Ikaros". J. Biol. Chem.277 (15): 13007–15. doi:10.1074/jbc.M111371200. PMID11799125.
Dorsam G, Goetzl EJ (2002). "Vasoactive intestinal peptide receptor-1 (VPAC-1) is a novel gene target of the hemolymphopoietic transcription factor Ikaros". J. Biol. Chem.277 (16): 13488–93. doi:10.1074/jbc.M107922200. PMID11812772.