ABDB-LIKE HOX PROTEINS STABILIZE DNA-BINDING BY THE MEIS1 HOMEODOMAINPROTEINS

Recent studies show that Hox homeodomain proteins from paralog groups 1 to 10 gain DNA binding specificity and affinity through cooperative binding with the divergent homeodomain protein Pbx1. However, the AbdB -like Hox proteins from paralogs 11, 12, and 13 do not interact with P bx1a, raising the possibility of different protein partners. The Meis1 homeobox gene has 44% identity to Pbx within the homeodomain and was identified as a common site of viral integration in myeloid leukemias arising in BXH-2 mire, These integrations result in constitutive activ ation of Meis1. Furthermore, the Hoxa-9 gene is frequently activated b y viral integration in the same BXH-2 leukemias, suggesting a biologic al synergy between these two distinct classes of homeodomain proteins in causing malignant transformation. We novi show that the Hoxa-9 prot ein physically interacts with Meis1 proteins by forming heterodimeric binding complexes on a DNA target containing a Meis1 site (TGACAG) and an AbdB-like Hox site (TTTTACGAC). Hox proteins from the other AbdB-l ike paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA bi nding complexes with Meis1b, while Hox proteins from other paralogs do not appear to interact with Meis1 proteins. DNB binding complexes for med by Meis1 with Hox proteins dissociate much more slowly than DNA co mplexes with Meis1 alone, suggesting that Hox proteins stabilize the i nteractions of Meis1 proteins with their DNA targets.