Human acute myeloid leukemia stem cells.
Acute myeloid leukemia (AML) is a clonal disorder defined by the accumulation of abnormally differentiated myeloid cells that are not mature; any myeloid lineage can be affected and the extent of maturation of the leukemia blasts can also vary. Because mature blast cells of AML have very limited proliferative capacity, it is believed that the leukemic clone is perpetuated by a rare population of leukemia stem cells (LSC) that have acquired a dramatic increase in their ability to self-renew. Elucidating the nature of the target cell that undergoes leukemic transformation and the resultant LSC that can initiate and maintain AML is essential for both the understanding of the leukemogenic process and for the design of effective therapies. However, identifying such cells using only clinical data from human subjects has been difficult due to obvious restriction in experimental intervention in humans. In addition, before clinical symptoms are presented, it is virtually impossible to acquire a complete picture of the early events in leukemogenesis. Other experimental approaches involved the study of naturally occurring or induced animal (murine) leukemias. While many aspects of these animal leukemias reproduced the human disease, there were also inconsistencies. The advent of xenotransplantation to accurately model human AML growing within an animal system has provided an important tool to begin to answer the fundamental questions regarding AML. This review will examine the work done using the xenograft system to characterize the nature of the leukemic clone and will specifically highlight the advances made in phenotypically, molecularly, and functionally defining the LSC. Finally, a variety of novel AML therapeutics aimed at eradicating the LSC will be discussed.
Hope
Kristin J
KJ
Division of Cell and Molecular Biology, University Health Network, and Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada.
Jin
Liqing
L
Dick
John E
JE
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014183:Transplantation, Heterologous