Regulator of myeloid differentiation and function: The secret life of Ikaros

Figure 1 Ikaros isoforms. The Ikaros gene in mice (Ikzf1) and humans (IKZF1) includes eight coding exons (exons 2-8 and 3B) and one upstream exon that is not translated (Figure 1). The untranslated exon (shown in red) has not been identified in initial reports, and the alternate exon designations that have appeared in early reports are shown at the bottom of the figure. Exon 3B is currently not identified as an exon in Genbank. Splice forms that include exon 3B have been designated as “plus” forms and many such splice forms, in addition to the ones shown, have been identified at the protein and/or mRNA level (i.e. Ik-x⁺, Ik-2⁺, Ik-4⁺, Ik-7⁺, Ik-8⁺) in humans and mice. An alternate splice site gives rise to splice forms that lack the last 30 bases of exon 7 (indicated with an X). Such splice variants have been designated minus forms (e.g. Ik-1^- and Ik-x^-). The four N-terminal zinc fingers (shown in blue) contribute to DNA binding and the two C-terminal zinc fingers (shown in black) are responsible for dimerization[1,2,19,47-53].

Figure 2 Overview of Ikaros expression in hematopoiesis. The relative expression levels of Ikaros mRNA in hematopoietic progenitors (light gray box in foreground) are indicated by levels of green shading. Progenitors from both the classic and the LMPP pathways are included. Relative Ikaros expression levels are from studies by Yoshida et al[63] that have used mice with an Ikaros reporter cassette [green fluorescent protein (GFP) down stream of an Ikaros promoter] as an indicator of Ikaros mRNA expression in early stages of murine hematopoiesis. Shown in the dark gray box in the background is the protein level expression of human Ikaros isoforms in differentiated hematopoietic cells and in Lin^-CD34⁺ hematopoietic progenitors as described by Ronniet al[19] and Payne et al[54]. Human cells that express Ik-x and/or Ik-1 also express the plus form of these isoforms[19,54] (i.e. Ik-1⁺/Ik-H and Ik-x⁺, see Figure 1). ¹Mature T cells express little Ikaros protein unless they are activated[19,54]. HSC: Hematopoietic stem cell; LT-HSC: Long-term-HSC; ST-HSC: Short-term-HSC; CMP: Common myeloid progenitor; GMP: Granulocyte/macrophage progenitor; LMPP: Progenitor with lymphoid and myeloid potential; MEP: Megakaryocyte/erythroid progenitor; LP: Lymphoid progenitor; NK: Natural killer.