The Oncoprotein E2A-Pbx1a Collaborates with Hoxa9 To Acutely Transform Primary Bone Marrow Cells

Abstract

A recurrent translocation between chromosome 1 (Pbx1) and 19 (E2A) leading to the expression of the E2A-Pbx1 fusion oncoprotein occurs in ∼5 to 10% of acute leukemias in humans. It has been proposed that some of the oncogenic potential of E2A-Pbx1 could be mediated through heterocomplex formation with Hox proteins, which are also involved in human and mouse leukemias. To directly test this possibility, mouse bone marrow cells were engineered by retroviral gene transfer to overexpress E2A-Pbx1a together with Hoxa9. The results obtained demonstrated a strong synergistic interaction between E2A-Pbx1a and Hoxa9 in inducing growth factor-independent proliferation of transduced bone marrow cells in vitro and leukemic growth in vivo in only 39 ± 2 days. The leukemic blasts which coexpress E2A-Pbx1a and Hoxa9 showed little differentiation and produced cytokines such as interleukin-3, granulocyte colony-stimulating factor, and Steel. Together, these studies demonstrate that the Hoxa9 and E2A-Pbx1a gene products collaborate to produce a highly aggressive acute leukemic disease.

ACKNOWLEDGMENTS

This work was supported by a grant from the National Cancer Institute of Canada. Unnur Thorsteinsdottir is the recipient of a Leukemia Research Fund of Canada fellowship, and Guy Sauvageau is an MRC Clinician-Scientist Scholar.

We acknowledge Corey Largman and Jeffrey Lawrence for their generous gift of anti-serum to Hoxa9. In addition, we acknowledge Mireille Mathieu and François Letendre, l’Hôpital Hôtel-Dieu de Montréal, for their assistance with peripheral blood counts and histochemistry, and we thank Christiane Lafleur and Stephane Matte for their expertise and help regarding the maintenance and manipulation of the animals kept at the specific-pathogen-free facility of the IRCM. The support of Nathalie Tessier is also acknowledged for FACS analyses.