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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2673-2680

HEMATOPOIESIS

Forced expression of the Ikaros 6 isoform in human placental blood CD34+ cells impairs their ability to differentiate toward the B-lymphoid lineage

Cécile Tonnelle, Florence Bardin, Christine Maroc, Anne-Marie Imbert, Fanny Campa, Ali Dalloul, Christian Schmitt, and Christian Chabannon

From the Institut Paoli-Calmettes, Centre Régional de Lutte Contre le Cancer Provence-Alpes-Côte d'Azur, Marseille, France; and Laboratoire d'Immunologie Cellulaire, UMR7627 Centre National de la Recherche Scientifique, Hôpital Pitié-Salpêtrière, Paris, France.

Studies in mice suggest that the Ikaros (Ik) gene encodes several isoforms and is a critical regulator of hematolymphoid differentiation. Little is known on the role of Ikaros in human stem cell differentiation. Herein, the biological consequences of the forced expression of Ikaros 6 (Ik6) in human placental blood CD34+ progenitors are evaluated. Ik6 is one of the isoforms produced from the Ikaros premessenger RNA by alternative splicing and is thought to behave as a dominant negative isoform of the gene product because it lacks the DNA binding domain present in transcriptionally active isoforms. The results demonstrate that human cord blood CD34+ cells that express high levels of Ik6 as a result of retrovirally mediated gene transfer have a reduced capacity to produce lymphoid B cells in 2 independent assays: (1) in vitro reinitiation of human hematopoiesis during coculture with the MS-5 murine stromal cell line and (2) xenotransplantation in nonobese diabetic-severe combined immunodeficient mice. These results suggest that Ikaros plays an important role in stem cell commitment in humans and that the balance between the different isoforms is a key element of this regulatory system; they support the hypothesis that posttranscriptional events can participate in the control of human hematopoietic differentiation.

© 2001 by The American Society of Hematology.
 

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