Submitted July 10, 2007
Accepted October 4, 2007
The role of Ikaros in human erythroid differentiation
Marilyne Dijon, Florence Bardin, Anne Murati, Michele Batoz, Christian Chabannon, and Cecile Tonnelle*
Centre de Therapie Cellulaire et Genique, Institut Paoli-Calmettes, Marseilles, France
Departement de Biopathologie, Institut Paoli-Calmettes, Marseilles, France
INSERM U576, Hopital L'Archet, Nice, France
Centre de recherche en cancerologie de Marseille, INSERM, U599, Marseilles, France
Universite de la Mediterranee, Marseilles, France
* Corresponding author; email: tonnellec{at}marseille.fnclcc.fr.
Ikaros - a factor that positively or negatively controls gene transcription - is active in murine adult erythroid cells, and involved in fetal to adult globin switching. Mice with Ikaros mutations have defects in erythropoiesis and anemia. In this paper, we have studied the role of Ikaros in human erythroid development, for the first time. Using a gene-transfer strategy, we expressed Ikaros 6 (Ik6) - a known dominant negative protein that interferes with normal Ikaros activity - in cord blood or apheresis CD34+ cells that were induced to differentiate along the erythroid pathway. Lentivirally-induced Ik6 forced expression resulted in increased cell death, decreased cell proliferation; decreased expression of erythroid-specific genes including GATA1, fetal and adult globins. In contrast, we observed the maintenance of a residual myeloid population that can be detected in this culture system, with a relative increase of myeloid genes expression, including PU1. In secondary cultures, expression of Ik6 favored reversion of sorted and phenotypically defined erythroid cells into myeloid cells, and prevented reversion of myeloid cells into erythroid cells. We conclude that Ikaros is involved in human adult or fetal erythroid differentiation, as well as in the commitment between erythroid and myeloid cells.
