The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/11/1201/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 9, November 1, 1999 1201-1214

Original Article

Defects in Hemopoietic Stem Cell Activity in Ikaros Mutant Mice

Aliki Nichogiannopouloua, Maryanne Trevisana, Steve Nebenb, Christoph Friedricha, and Katia Georgopoulosa
a Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129
b Bayer Corporation, Biotechnology Division, Berkeley, California 94710

Correspondence to: Katia Georgopoulos, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129. Tel:617-726-4445 Fax:617-726-4453 E-mail:katia_georgopoulos{at}cbrc.mgh.harvard.edu.

Here we provide evidence that the Ikaros family of DNA binding factors is critical for the activity of hemopoietic stem cells (HSCs) in the mouse. Mice homozygous for an Ikaros null mutation display a >30-fold reduction in long-term repopulation units, whereas mice homozygous for an Ikaros dominant negative mutation have no measurable activity. The defect in HSC activity is also illustrated by the ability of wild-type marrow to repopulate unconditioned Ikaros mutants. A progressive reduction in multipotent CFU-S14 (colony-forming unit-spleen) progenitors and the earliest erythroid-restricted precursors (BFU-E [burst-forming unit-erythroid]) is also detected in the Ikaros 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 progeny or a negative role of Ikaros at later stages of erythromyeloid differentiation. In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors flk-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 contribute to the early hemopoietic phenotypes manifested in the absence of Ikaros.

Key Words: transcription factors, hemopoiesis, flk2, c-kit regulation


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