Molecularly and phenotypically, the induced mice apparently passed through two linked but separate disease states. Initially, AE expression reprogrammed haematopoietic stem cells (HSC) to produce huge numbers of myeloid cells. Next generation sequencing further revealed that the initial “lineage instruction stage” was followed by a second wave of transcriptional rewiring, altering key cancer check points and inactivating cell death safety mechanisms. The pathways and molecular switches identified in mice were also found to be specifically deregulated in the majority of human CBF-AML patients, qualifying them as lead structures for designing new therapies. The experimental findings that HSC-like and more differentiated blasts are capable of initiating and maintaining leukaemia also directly implies that chemotherapy or emerging targeted therapies used for eradicating CBF-AML must target both LSC subsets to be effective.
Because the mouse model generated by Cabezas-Wallscheid and collaborators allowed for reversing AE expression during manifest leukemia, it was possible to ask the clinically important question if ablation of AE function can have a therapeutic benefit. Indeed, when AE was inactivated in leukemic mice, several animals showed clear signs of disease remission. The finding that inactivation of AE function is a potential therapeutic option warrants the future development of AE-specific therapeutic strategies.
The complete results of this summary will shortly be published in the forthcoming issue of EMBO Molecular Medicine (EMBO Mol Med 2013 5, 1–17) and are available as an early view at http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302661/pdf.