Advances in acute myeloid leukemia differentiation therapy: A critical review

[Display omitted] •Differentiation and self-renewal of AML cells are uncoupled.•Inducing differentiation per se is not sufficient for curing AML.•Mature leukemia-derived cells can de-differentiate into immature AML blasts.•Eradicating all maturation states of AML cells is fundamental for durable and efficacious therapy.•Morphological and/or immunophenotypic analysis of differentiation markers may underestimate the actual burden of AML. Acute myeloid leukemia (AML) is characterized by impaired differentiation and indefinite proliferation of abnormal myeloid progenitors. Although differentiating agents were deemed to revolutionize AML therapy, most treated non-APL AML patients are refractory or relapse. According to cancer stem cell model, leukemia-initiating cells are the root cause of relapse given their unidirectional potential to generate differentiated AML blasts. Nonetheless, accumulating evidences emphasize the de-differentiation plasticity and leukemogenic potential of mature AML blasts and the frailty of targeting leukemic stem cells per se. This review critically discusses the potential and challenges of (lessons learnt from) conventional and novel differentiating agents in AML therapy. Although differentiating agents might hold promise, they should be exploited within the context of a rationale combination regimen eradicating all maturation/differentiation states of AML cells. The results of the routinely used immunophenotypic markers and/or morphological analyses of differentiation should be carefully interpreted given their propensity to underestimate AML burden.