HOXA9 TRANSFORMS PRIMARY BONE-MARROW CELLS THROUGH SPECIFIC COLLABORATION WITH MEIS1A BUT NOT PBX1B

Hoxa9, Meis1 and Pbx1 encode homeodomain-containing proteins implicate d in leukemic transformation in both mice and humans. Hoxa9, Meis1 and Pbx1 proteins have been shown to physically interact with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and w ith Pbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA. In this study, we sought to determine if Hoxa9 cou ld transform hemopoietic cells in collaboration with either Pbx1 or Me is1. Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1a simultaneously, induced growth factor-dependent olig oclonal acute myeloid leukemia in <3 months when transplanted into syn genic mice. In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alon e, or the combination of Hoxa9 and Pbx1b failed to transform these cel ls acutely within 6 months posttransplantation. Similar results were o btained when FDC-P1 cells, engineered to overexpress these genes, were transplanted to syngenic recipients. Thus, these studies demonstrate a selective collaboration between a member of the Hox family and one o f its DNA-binding partners in transformation of hemopoietic cells.