Non-genetic mechanisms of drug resistance in acute leukemias

HighlightsNon-genetic mechanisms contribute to disease and drug response heterogeneity in acute leukemias and represent therapeutic vulnerabilities.Leukemia cells can evade immune- and antibody-based therapies through antigen loss, therefore boosting surface antigen expression can further enhance its efficacy.Recent advances in developing effective combination therapies to improve drug synergies and survival outcome in acute myeloid leukemia (AML).Advances in genomic and molecular profiling of patient cohorts allow identification of biomarkers to predict drug response.AbstractAcute leukemia is characterized by clonal heterogeneity that contributes to poor drug responses in patients. Despite treatment advances, the occurrence of relapse remains a major barrier to achieving cures as current therapeutic approaches are inadequate to effectively prevent or overcome resistance. Given that only a few genetic mutations are associated with relapse in acute leukemia patients, there is a growing focus on 'non-genetic' mechanisms that affect the hallmarks of cancer to allow leukemic cells to survive post therapy. In this review, we provide an overview of the therapeutic landscape in acute leukemias. Importantly, we discuss non-genetic mechanisms exploited by leukemic cells to promote their survival after treatment. Last, we present current strategies to prevent or overcome drug resistance in this disease.