The oncoprotein E2A-Pbx1a collaborates with Hoxa9 to acutely transform primary bone marrow cells

A recurrent translocation between chromosome 1 (Pbx1) and 19 (E2A) leading to the expression of the E2A-Phx1 fusion oncoprotein occurs in similar to 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 fo rmation with Hox proteins, which are also involved in human and mouse leuke mias. To directly test this possibility, mouse bone marrow cells were engin eered by retroviral gene transfer to overexpress E2A-Pbx1a together with Ho xa9. The results obtained demonstrated a strong synergistic interaction bet ween E2A-Pbx1a and Hoxa9 in inducing growth factor-independent proliferatio n of transduced bone marrow cells in vitro and leukemic growth in vivo in o nly 39 +/- 2 days. The leukemic blasts which coexpress E2A-Pbx1a and Hoxa9 showed little differentiation and produced cytokines such as interleukin3, granulocyte colony-stimulating factor, and Steel. Together, these studies d emonstrate that the Hoxa9 and E2A-Pbx1a gene products collaborate to produc e a highly aggressive acute leukemic disease.