Defects in hemopoietic stem cell activity in Ikaros mutant mice

Here we provide evidence that the Ikaros family of DNA binding factors is c ritical for the activity of hemopoietic stem cells (HSCs) in the mouse. Mic e homozygous for an Ikaros null mutation display a >30-fold reduction in lo ng-term repopulation units, whereas mice homozygous for an Ikaros dominant negative mutation have no measurable activity. The defect in HSC activity i s also illustrated by the ability of wild-type marrow to repopulate uncondi tioned Ikaros mutants. A progressive reduction in multipotent CFU-S,, (colo ny-forming unit-spleen) progenitors and the earliest erythroid-restricted p recursors (BFU-E [burst-forming unit-erythroid]) is also detected in the Ik aros mutant strains consistent with the reduction in HSCs. Nonetheless, the more mature clonogenic erythroid and myeloid precursors are less affected, indicating either the action of a compensatory mechanism to provide more p rogeny or a negative role of Ikaros at later stages of erythromyeloid diffe rentiation. In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors fk-2 and c-kit is observed in the lineage-depleted c-kit( +)Sca-1(+) population that is normally enriched for HSCs and may in part co ntribute to the early hemopoietic phenotypes manifested in the absence of I karos.