We have developed a novel model of human AML based on retroviral transduction of primary human CD34+ umbilical cord blood cells with a gene encoding the product of the t(9:11) translocation, MLL-AF9. When these cells are transplanted into immunodeficient mice, they give rise to either AML or ALL. The type of leukemia is dependent on environmental cues, provided by in vitro culture conditions or the use of humanized mice expressing human cytokines.
We are also continuing to build on the mouse model system by testing and creating additional immunodeficient mouse strains. The NOD / SCID (NS) mouse has been the gold standard for some time for human xenograft of normal and leukemic cells. These mice disproportionately promote lymphoid differentiation of human cells in vivo. A variant mouse expressing the human cytokines SCF, GM-CSF and IL-3 (NSS) allows for a more myeloid tolerant environment. We have exploited this difference to allow predictable modeling of AML development in vivo.
Another more severely immunodeficient strain of mouse, NS-gammac-/- (NSG), is now available that is more suitable for xenograft studies due to better engraftment of human cells. However, this mouse also disproportionately promotes lymphoid development. We have developed the NSGS mouse, which combines the enhanced receptivity to human engraftment of the NSG and promotes increased human myeloid cell expansion similar to NSS. We expect that this new mouse will allow for easier, more consistent modeling of human patient AML in vivo.