Defining Roles for HOX and MEIS1 Genes in Induction of Acute Myeloid Leukemia

Abstract

Complex genetic and biochemical interactions between HOX proteins and members of the TALE (i.e., PBX and MEIS) family have been identified in embryonic development, and some of these interactions also appear to be important for leukemic transformation. We have previously shown that HOXA9 collaborates withMEIS1 in the induction of acute myeloid leukemia (AML). In this report, we demonstrate that HOXB3, which is highly divergent from HOXA9, also genetically interacts withMEIS1, but not with PBX1, in generating AML. In addition, we show that the HOXA9 and HOXB3genes play key roles in establishing all the main characteristics of the leukemias, while MEIS1 functions only to accelerate the onset of the leukemic transformation. Contrasting the reported functional similarities between PREP1 and MEIS1, such as PBX nuclear retention, we also show that PREP1 overexpression is incapable of accelerating the HOXA9-induced AML, suggesting that MEIS1 function in transformation must entail more than PBX nuclear localization. Collectively, these data demonstrate thatMEIS1 is a common leukemic collaborator with two structurally and functionally divergent HOX genes and that, in this collaboration, the HOX gene defines the identity of the leukemia.

ACKNOWLEDGMENTS

We acknowledge Nadine Mayotte for expert technical assistance and Marie-Eve Leroux and Stephane Matte for their expertise and help regarding the maintenance and manipulation of the animals kept at the specific-pathogen-free facility. The support of Nathalie Tessier is also acknowledged for FACS analyses. Robert G. Hawley is acknowledged for his MSCV vectors.

This work was supported by a grant from the National Cancer Institute of Canada (NCI-C). U.T. is the recipient of a Leukemia Research Fund of Canada Fellowship, E.K. is the recipient of a Leukemia and Lymphoma Society of America Fellowship, L.J. is the recipient of a Medical Research Council (MRC) of Canada Fellowship, and Guy Sauvageau is an MRC Clinician-Scientist Scholar.