Acute myeloid leukemia: leukemia stem cells write a prognostic signature

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by a proliferation of primitive myeloid cells or 'blasts' in the blood. Although highly variable, most patients with AML will achieve a remission but later relapse and die from the disease. It is an extremely heterogeneous disease at the morphological, molecular and clinical levels with many distinct subgroups. Due to this heterogeneity, classification is critical to provide prognostic data informing risk-adapted therapeutic strategies, which have improved outcome dramatically in some subtypes of AML [1].To date, cytogenetic abnormalities have provided most prognostic information, although up to 50% of patients have a normal karyotype [2]. In addition, over the past decade the detection of specific molecular mutations, including mutations in the NPM1 and FLT-3 genes, have provided additional prognostic information to predict relapse and overall survival. Global gene expression profiles of bulk leukemia cells have provided further data to improve classification and prognosis [3,4], and have identified overexpression of specific genes, such as BAALC and ERG, to be associated with poor survival. These studies have aided our understanding of the biology of AML as a disease characterized by transcriptional dysregulation [5].Our understanding of the organization of malignancy and the basis of therapeutic failure have recently been informed by the demonstration that certain malignancies are arranged in hierarchies and have a cancer stem or initiating cell at their apices, which propagates and maintains the tumor [6]. The cancer stem cell hypothesis is controversial in some solid organ malignancies but is well accepted in leukemias, and AML was the first malignancy in which a cancer stem cell was demonstrated [7,8]. The malignant hierarchy in AML is similar to normal hematopoietic ontogeny, with leukemia stem cells (LSCs) in most AML patients being positive for the surface marker CD34, as a