Developmental-stage-dependent transcriptional response to leukaemic oncogene expression

• Published in: Nature communications 2015-05, Vol.6 (1), p.7203, Article 7203
• Main Authors: Regha, Kakkad, Assi, Salam A., Tsoulaki, Olga, Gilmour, Jane, Lacaud, Georges, Bonifer, Constanze
• Format: Article
• Language: English
• Subjects: 13/100; 13/31; 38/39; 631/208/726/2102; 631/67/1990/283/1897; 631/67/395; Animals; Blood; Blotting, Western; Cell Culture Techniques; Chromatin Immunoprecipitation; Core Binding Factor Alpha 2 Subunit - genetics; DNA-Binding Proteins - genetics; Electroporation; Epigenetics; Flow Cytometry; Gene expression; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Neoplastic - genetics; Gene Regulatory Networks; Hematopoiesis - genetics; Humanities and Social Sciences; In Vitro Techniques; Leukemia; Leukemia, Myeloid, Acute; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; multidisciplinary; Mutation; Oncogene Proteins, Fusion - genetics; Proteins; Proto-Oncogene Proteins - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Stem cells; Transcription Factors - genetics; Transcriptome; Translocation, Genetic
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8203

Acute myeloid leukaemia (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 that gives rise to the RUNX1-ETO fusion protein and initiates the most common form of human AML. Here we study the differentiation of mouse embryonic stem cells expressing an inducible RUNX1-ETO gene into blood cells as a model, combined with genome-wide analyses of transcription factor binding and gene expression. 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 developmental stage specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit. Acute myeloid leukaemia often originates from a chromosomal translocation creating a RUNX1/ETO fusion protein. Here Regha et al , generate a mouse stem cell model and demonstrate the fusion protein disrupts transcription in a differentiation-stage-specific manner.