Leukemic Stem Cells: Where do They Come From?

Leukemias can now be viewed as aberrant hematopoietic processes initiated by rare cancer stem cells, or leukemic stem cells (LSCs) that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LSCs and the mechanisms responsible for their emergence in the course of the disease. Mouse models of human leukemias have provided a unique system to study the mechanisms influencing LSC generation and function, and were recently used to demonstrate that LSCs can arise from both self-renewing hematopoietic stem cells (HSCs) and committed progenitor populations. This striking finding indicates that LSC identity is largely dictated by the nature of the oncogenic events and by how these events perturb essential processes such as self-renewal, proliferation, differentiation, and survival. Such approaches in the mouse are essential for the basic understanding of leukemogenesis and for the conceptual design of novel therapeutic strategies that could lead to improved treatments for human leukemias.