After decades during which the treatment of
acute myeloblastic leukemia was limited to variations around a skeleton of
cytarabine/
anthracycline, targeted
therapies appeared. These
therapies, first based on
monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of
leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-
tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the
tumor heterogeneity inherent to
leukemia and the clonal drift of which this type of
tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of
leukemia, either spontaneous or under
therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to
therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different
tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/
immunotherapy ("pan-resistant clones"), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the
tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the
leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-
chemotherapy of remaining leukemic cells.