BOTH PBX1 AND E2A-PBX1 BIND THE DNA MOTIF ATCAATCAA COOPERATIVELY WITH THE PRODUCTS OF MULTIPLE MURINE HOX GENES, SOME OF WHICH ARE THEMSELVES ONCOGENES

E2A-PBX1 is the oncogene produced at the t(1;19) chromosomal breakpoin t of pediatric pre-B-celI leukemia. Expression of E2A-Pbx1 induces fib roblast transformation and myeloid and T-cell leukemia in mice and arr ests differentiation of granulocyte macrophage colony-stimulating fact or-dependent myeloblasts in cultured marrow. Recently, the Drosophila melanogaster protein Exd, which is highly related to Pbx1, was shown t o bind DNA cooperatively with the Drosophila homeodomain proteins Ubx and Abd-A. Here, we demonstrate that the normal Pbx1 homeodomain prote in, as well as its oncogenic derivative, E2A-Pbx1, binds the DNA seque nce ATCAATCAA cooperatively with the murine Hox-A5, Hox-B7, Hox-B8, an d Hox-C8 homeodomain proteins, which are themselves known oncoproteins , as well as with the Hox-D4 homeodomain protein. Cooperative binding to ATCAATCAA required the homeodomain-dependent DNA-binding activities of both Pbx1 and the Hox partner. In cotransfection assays, Hox-BI su ppressed transactivation by E2A-Pbx1. These results suggest that (i) P bx1 may participate in the normal regulation of Hox target gene transc ription in vivo and therein contribute to aspects of anterior-posterio r patterning and structural development in vertebrates, (ii) that E2A- Pbx1 could abrogate normal differentiation by altering the transcripti onal regulation of Hox target genes in conjunction with Hox proteins, and (iii) that the oncogenic mechanism of certain Hox proteins may req uire their physical interaction with Pbx1 as a cooperating, DNA-bindin g partner.