p210^BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription

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.