NSG mice are not prone to development of thymomas and have an increased lifespan ( 12).

More recently, reports have demonstrated that a targeted deletion in the γ-common chain in NOD/SCID mice (NSG mice) results in the elimination of residual NK cell activity and provides an improved environment for growth and development of human cells ( 12, 13). Newer strains of mice engineered with targeted deletion of the β 2-microglobulin gene within a NOD/SCID background have resulted in models with decreased NK cell function better suited for studying the progression of diseases such as human AML ( 11). In addition, prolonged engraftment of leukemic cells in this breed of mice was limited by the development of spontaneous thymic lymphomas and a reduced life span ( 9, 10). For AML, however, the engraftment levels in NOD/SCID mice are frequently low, with typical levels ranging from 0.1% to 10% of the mouse BM ( 7). Over the last 15 years, immunocompromised mice, such as NOD/SCID mice, have been the model of choice to study morphological and biological characteristics of human AML and other cancers in vivo ( 3, 7, 8). This result has challenged the original concept(s) of cancer stem cell. In contrast to earlier results, they demonstrate that single melanoma cells, regardless of phenotype, can reconstitute the disease in this more immunocompromised mouse strain. However, Quintana and colleagues recently reevaluated these results using NOD/SCID/IL2Rγc null mice ( 6). Subsequent work in other malignancies, also using the NOD/SCID mouse as a model, suggested similar conclusions for breast and colon cancers ( 4, 5). Based on these data, they suggested that LSCs are rare, capable of partial differentiation, and restricted to the immature phenotype associated with hematopoietic stem cells in normal blood differentiation. In 1997, Bonnet and Dick observed that only CD34 +CD38 – cells were able to reconstitute human acute myelogenous leukemia (AML) in nonobese diabetic mice with severe combined immunodeficiency (NOD/SCID mice) ( 2, 3). Leukemic stem cells (LSCs) were the first cancer stem cells described, and studies of LSCs have been instrumental in developing the definition of cancer stem cells ( 1). These results suggest a plasticity of the cancer stem cell phenotype that we believe has not been previously described. These results indicate that human AML stem cells are rare and enriched but not restricted to the phenotype associated with normal primitive hematopoietic cells. While SL-ICs were enriched in the Lin –CD38 – fraction compared with the other fractions analyzed, SL-ICs in this fraction represented only one-third of all SL-ICs present in the unfractionated specimen. Remarkably, each engrafting fraction consistently recapitulated the original phenotypic diversity of the primary AML specimen and contained self-renewing leukemic stem cells, as demonstrated by secondary transplants. In contrast to previous results, SL-ICs were found among cells expressing lineage markers (i.e., among Lin + cells), CD38, or CD45RA, all markers associated with normal committed progenitors. Using a robust model of xenotransplantation based on NOD/SCID/IL2Rγc-deficient mice, we confirmed that human leukemic stem cells, functionally defined by us as SCID leukemia-initiating cells (SL-ICs), are rare in acute myelogenous leukemia (AML). However, recent work in other types of tumors has challenged the cancer stem cell model. Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic progenitors or stem cells.

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