Cell stage dependent transcriptional response to leukemic oncogene

Acute myeloid leukemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation which gives rise to the RUNX1/ETO fusion protein and initiates the most common form of human AML. To understand the molecular principles governing this differential action, we used the differentiation of mouse embryonic stem cells expressing an inducible RUNX1/ETO protein into blood cells as a traceable model combined with genome-wide analyses of transcription factor binding and gene expression. We found that RUNX1/ETO interferes with both the activating and repressive function of its normal counterpart, RUNX1, at early and late stages of blood cell development. However, the response of the transcriptional network to RUNX1/ETO expression is stage-specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit. Microarray data have been used to study RUNX1/ETO role in hematopoietic system