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.
Buet
D
D
INSERM, U790, Institut Gustave Roussy, Villejuif, France.
Raslova
H
H
Geay
J-F
JF
Jarrier
P
P
Lazar
V
V
Turhan
A
A
Morlé
F
F
Vainchenker
W
W
Louache
F
F
D002454:Cell Differentiation; D015536:Down-Regulation; D041905:Erythroid Cells / Q000166:cytology*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology*; D014158:Transcription, Genetic; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000235:genetics
C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D016044:Fusion Proteins, bcr-abl