The Development of Personalized Medicine: Acute Myeloid Leukemia as a Model

The term personalized medicine has been employed in widely different contexts and has acquired status as one of the most often used keywords recently. In this review we take it to understand the application of modern diagnostic medicine and therapeutics to patient with the purpose of eradicating disease or alleviating symptoms in a manner, where all actions are based on detailed knowledge of the condition of the individual patient. Applying these concepts should lead to optimization of clinical decision-making and, in its utmost consequence, a substantial decrease in costs incurred for hospitalization and follow-up. The latter is based on the evidence that for many disorders “less but more targeted” will mean improved outcome. Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is a major challenge in terms of diagnosis, care, follow-up and therapy. Thus, in population-based analyses, overall survival is only just exceeding 40% with major reasons for treatment failure. For these reasons, AML has been intensely studied during the recent decades. With the development of multiparametric flow cytometry, it allows us to get an accurate diagnosis and immunophenotypic profiles of AML. In addition, there is now an abundance of knowledge regarding its cytogenetic and molecular background. These enable us to follow the amount of disease down to the minutest quantity with a high resolution of molecular details. Finally, based on knowledge of these variables in the single patient cytoreduction is now being refined to therapies targeted to the molecular changes in the patient

Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human mutant AML and the corresponding mouse model, we identified , encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target