1. ¹INSERM, U790, Institut Gustave Roussy, Villejuif, France
2. ²Université –Paris XI, Orsay, France
3. ³Institut Gustave Roussy, Villejuif, France
4. ⁴Institut Gustave Roussy, Unité de Génomique Fonctionnelle, Villejuif, France
5. ⁵UPRES EA3805, Université Jean Bernard, 2 Rue de la Milétrie, Poitiers, France
6. ⁶CNRS, UMR 5534, Centre de Génétique Moléculaire et Cellulaire, Université Lyon 1, Villeurbanne, France

Correspondence: Dr F Louache, Department of Hematopoiese and cellules Souches, INSERM U790, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: fawl@igr.fr

Received 16 August 2006; Revised 19 December 2006; Accepted 9 January 2007; Published online 22 February 2007.

Abstract

The BCR-ABL oncoprotein exhibits deregulated protein tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph)-positive human leukemias. Here, we report that ectopic expression of p210^BCR-ABL in the megakaryoblastic Mo7e cell line and in primary human CD34⁺ progenitors trigger erythroid differentiation at the expense of megakaryocyte (MK) differentiation. Clonal culture of purified CD41⁺CD42^- cells, a population highly enriched in MK progenitors, combined with the conditional expression of p210^BCR-ABL tyrosine kinase activity by imatinib identified a true lineage reprogramming. In both Mo7e or CD41⁺CD42^- cells transduced with p210^BCR-ABL, lineage switching was associated with a downregulation of the friend leukemia Integration 1 (FLI-1) transcription factor. Re-expression of FLI-1 in p210^BCR-ABL-transduced Mo7e cells rescued the megakaryoblastic phenotype. Altogether, these results demonstrate that alteration of signal transduction via p210^BCR-ABL reprograms MK cells into erythroid cells by a downregulation of FLI-1. In addition, our findings underscore the role of kinases in lineage choice and infidelity in pathology and suggest that downregulation of FLI-1 may have important implications in CML pathogenesis.