Ohlsson, Ewa5; Hasemann, Marie Sigurd5; Willer, Anton5; Lauridsen, Felicia Kathrine Bratt5; Rapin, Nicolas Philippe Jean-Pierre6; Jendholm, Lars Johan5; Porse, Bo Torben7
1 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet2 The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet3 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet6 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet7 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL-induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion-driven transformation and find that it sharply demarcates tumor initiation and maintenance.
Journal of Experimental Medicine, 2014, Vol 211, Issue 1, p. 5-13