Point: AML Stem Cells are Immature, Rare, and Targets for Curative Therapy in AML.

Abstract

Abstract SCI-34The cellular and molecular basis for the heterogeneity that exists within the individual cells that make up a tumour is not well understood. There is clear evidence from the historical literature of human experimentation, the vast majority of leukemia blasts are post-mitotic and generated from a rapidly proliferating fraction of <5% of total leukemic blasts. These same studies also established that a rare subfraction of blasts were quiescent and only entered cell cycle in the order of weeks or months. The cancer stem cell (CSC) model postulates that such heterogeneity arises because the tumour is organized as a cellular hierarchy sustained by a CSC at the apex. If a tumour is homogeneous the CSC model would not apply. By employing the principles of stem cell biology, first worked out in hematopoiesis, of clonal assays and prospective cell purification, there is solid evidence that human AML follows a CSC model. LSCs are the only AML cells capable of self-renewal while still generating rapidly proliferating progenitors and terminal leukemic blasts. Our studies have also demonstrated that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprised of distinct hierarchically arranged LSC classes. Distinct LSC fates derive from heterogeneous self-renewal potential. Finally, many LSC appear to be quiescent. Thus, the AML clone is organized as a hierarchy that originates from LSC, which produce AML-CFU and leukemic blasts. AML is organized as a cellular hierarchy sustained by LSCs at their apex. The rare occurrence, generally dormant nature, and abnormal apoptotic response of LSCs are all properties that may render them resistant to conventional chemotherapeutics that target proliferating cells. In addition, minimal residual disease occurrence and poor survival have been attributed to high LSC frequency at time of diagnosis in AML patients. Although there are a number of well known problems with xenotransplant assays, recent improvements to this model have been employed to assess both the frequency of LSC in a cross section of AML samples as well as the nature of the cell surface phenotype of the LSC. Collectively this research has shown that the LSC frequency can vary over many orders of magnitude from 1% to <1 per 106, with some genetic AML subtypes such as MLL leukemias possessing the highest LSC frequency. Thus even with the most optimized assay system they represent a rare subfraction of AML blasts for most forms of leukemia. The properties of AML-LSC make them especially resistant to standard cytoablative therapeutics, so LSC-targeted therapies are clearly needed to improve long term survival for this dismal disease. A number of new therapeutics are being developed and evaluated in the xenotransplant assays and several are now moving into clinical trial. With translation of lab-based research into the clinic, the next several years will begin to provide definitive answers to the most vexing question the continues to surround the whole field of cancer stem cells: while the importance of CSC are clearly seen in numerous xenotransplant models of leukemic and solid tumours, how relevant are they in the human disease? Dick JE. Stem cell concepts renew cancer research. Blood 2008;112:4793-807. DisclosuresDick:Roche: Research Funding; CSL Ltd: Research Funding.