Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia

Complex genetic and biochemical interactions between HOX proteins and membe rs of the TALE (i.e., PBX and MEIS) family have been identified in embryoni c development, and some of these interactions also appear to be important f or leukemic transformation. We have previously shown that HOX19 collaborate s with MEIS1 in the induction of acute myeloid leukemia (AML). In this repo rt, we demonstrate that HOXB3, which is highly divergent from HOXA9, also g enetically interacts with MEIS1, but not with PBX1, in generating AML. In a ddition, we show that the HOXA9 and HOXB3 genes play key roles in establish ing all the main characteristics of the leukemias, while MEIS1 functions on ly to accelerate the onset of the leukemic transformation. Contrasting the reported functional similarities between PREP1 and MEIS1, such as PBX nucle ar retention, we also show that PREP1 overexpression is incapable of accele rating the HOXA9-induced AML, suggesting that MEIS1 function in transformat ion must entail more than PBX nuclear localization. Collectively, these dat a demonstrate that MEIS1 is a common leukemic collaborator with two structu rally and functionally divergent HOX genes and that, in this collaboration, the HOX gene defines the identity of the leukemia.