LEUKEMIA STEM CELLS: STUDYING THE ROOT OF LEUKEMIA

A fundamental problem in cancer research is the identification of the cell type capable of initiating and sustaining the growth of the neoplastic clone in vivo. The key to solving this problem lies on the observation made over 40 years ago that tumors are heterogeneous and thus might be maintained only by a rare subset of cells called "cancer stem cells" (CSCs). However, the proof of this principle was only possible after the development of modern research tools for investigating the behavior of defined cell populations in vivo. The blood-related cancer leukemia was the first disease where human CSCs, or leukemic stem cells (LSCs), were isolated. The development of quantitative xenotransplantation assays using immune-deficient mouse recipients to detect primitive human hematopoietic stem cells (HSCs) with in vivo repopulating ability and the adaptation of this model to leukemia have been instrumental. Leukemia can now be viewed as aberrant hematopoietic processes initiated by rare 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 LSC and the mechanisms responsible for their emergence in the course of the disease. This report will review our current knowledge on normal and leukemic stem cell development and finally demonstrate how these discoveries provide a paradigm for identification of CSCs from solid tumors. By a careful comparative analysis of the properties of CSCs and of their normal counterparts, it should be possible to pinpoint critical features amenable to efficient anti-CSC therapies.