Acute myeloid leukemia (AML) is one of the most aggressive, clinically and biologically heterogenenous, hematological alignancies. The different genetics classify disease entities, and define the prognostic risk category to which AML patients are assigned and the treatment choices.There is one entity, the AML with nucleophosmin (NPM1) gene mutations, that accounts for onethird of all adult AML (the most frequent) and where another gene mutation - the Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) - acts as ‘tip of the balance’ for patients’ risk definition, drastically worsening the prognosis and hanging treatment in those 40% of patients where it is detected. This has been a main field of research of Prof. Maria Paola Martelli and her team since years and specifically of her ERC consolidator grant ContraNPM1AML. Here, she will exploit concepts stemming from her ERC funded studies on the key role of kinases in the NPM1-mutated AML development, response to therapy and initiating relapse, and focus on that 60% of patients regarded at favorable prognosis, who nevertheless in 40% of cases will relapse with extremely dismal outcome. Currently, successful strategies to identify novel frontline key markers to refine risk are not available. reMARK-AML takes the challenge and changes prognostic risk parameters, pointing at re-envisioning the marker at single-cell level. A first strategy has been designed and will be tested for the proof-of-concept in patients in a prospective non-interventional study. We have established contacts with industrial partners for the development of fit-for-purpose diagnostic assay prototypes to test then in the study. The success of reMARK-AML will open the next challenge of developing marketable diagnostic kits and defining a strong business plan in order to measure the impact of our idea and PoC in the real-world clinical setting.