MLL-AF9 (MA9) is a leukemia fusion gene formed upon translocation of the AF9 gene on chromosome 9 and the MLL gene on chromosome 11. MA9 is commonly found in acute myeloid leukemia (AML) and occasionally in acute lymphoid leukemia and is associated with intermediate to poor outcome. The specific signaling pathways downstream of MA9 are still poorly understood. We have recently described a model system whereby we expressed the MA9 fusion gene in human CD34+ Umbilical Cord Blood (UCB) cells and showed that these cells transformed to acute myeloid or lymphoid leukemia when injected into immunodeficient mice. The Mixed Lineage Leukemia oncogenes are unique in this model system in that they promote full transformation of primary human blood cells, while all other leukemia-associated oncogenes tested thus far have induced only partial phenotypes. Here we provide an update on the use of this system for modeling human leukemia and its potential application for therapeutic testing of novel compounds to treat the disease. We focus specifically on the Rho family of small guanosine triphosphatases (GTPases) as potential therapeutic targets, which we have implicated in the pathogenesis of AML associated with MA9 expression.