Dissecting the Genetic and Non-Genetic Heterogeneity of Acute Myeloid Leukemia Using Next-Generation Sequencing and In Vivo Models

SIMPLE SUMMARY: Acute myeloid leukemia (AML) is an extremely aggressive form of blood cancer with high rates of treatment failure. AML arises from the stepwise acquisition of genetic aberrations and is a highly heterogeneous disorder. Recent research has shown that individual AML samples often contain several clones that are defined by a distinct combination of genetic lesions, epigenetic patterns and cell surface marker expression profiles. A better understanding of the clonal dynamics of AML is required to develop novel treatment strategies against this disease. In this review, we discuss the recent developments that have further deepened our understanding of clonal evolution and heterogeneity in AML. ABSTRACT: Acute myeloid leukemia (AML) is an extremely aggressive and heterogeneous disorder that results from the transformation of hematopoietic stem cells. Although our understanding of the molecular pathology of AML has greatly improved in the last few decades, the overall and relapse free survival rates among AML patients remain quite poor. This is largely due to evolution of the disease and selection of the fittest, treatment-resistant leukemic clones. There is increasing evidence that most AMLs possess a highly complex clonal architecture and individual leukemias are comprised of genetically, phenotypically and epigenetically distinct clones, which are continually evolving. Advances in sequencing technologies as well as studies using murine AML models have provided further insights into the heterogeneity of leukemias. We will review recent advances in the field of genetic and non-genetic heterogeneity in AML.