MLL-AF9 leukemia stem cells: hardwired or taking cues from the microenvironment?

MLL rearrangements in humans lead to both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). While AML has been successfully produced in mice, modeling ALL has been more difficult. In this issue of Cancer Cell, Wei et al. (2008) describe generation of AML, ALL, and biphenotypic leukemia by manipulating the cytokine milieu of human progenitor cells expressing MLL-AF9. They demonstrate that both multipotent and lineage-restricted progenitors are targeted by MLL-AF9 fusion proteins and that Rac signaling is crucial for survival. This study demonstrates the heterogeneity of MLL-AF9 leukemic stem cells and the importance of the microenvironment in determining lineage outcome.