Ps. Knoepfler et al., MEIS1 AND PKNOX1 BIND DNA COOPERATIVELY WITH PBX1 UTILIZING AN INTERACTION SURFACE DISRUPTED IN ONCOPROTEIN E2A-PBX1, Proceedings of the National Academy of Sciences of the United Statesof America, 94(26), 1997, pp. 14553-14558
E2a-Pbx1 is a chimeric transcription factor oncoprotein produced by th
e t(1;19) translocation in human pre-B cell leukemia. Class I Hox prot
eins bind DNA cooperatively with both Pbx proteins and oncoprotein E2a
-Pbx1, suggesting that leukemogenesis by E2a-Pbx1 and Hox proteins may
alter transcription of cellular genes regulated by Pbx-Hox motifs. Li
kewise, in murine myeloid leukemia, transcriptional coactivation of Me
is1 with HoxA7/A9 suggests that Meis1-HoxA7/9 heterodimers may evoke a
berrant gene transcription. Here, we demonstrate that both Meis1 and i
ts relative, pKnox1, dimerize with Pbx1 on the same TGATT-GAC motif se
lected by dimers of Pbx proteins and unidentified partner(s) in nuclea
r extracts, including those from t(1;19) pre-B cells. Outside their ho
meodomains, Meis1 and pKnox1 were highly conserved only in two motifs
required for cooperativity with Pbx1. Like the unidentified endogenous
partner(s), both Meis1 and pKnox1 failed to dimerize significantly wi
th E2a-Pbx1. The Meis1/pKnox1-interaction domain in Pbx1 resided predo
minantly in a conserved N-terminal Pbx domain deleted in E2a-Pbx1. Thu
s, the leukemic potential of E2a-Pbx1 may require abrogation of its in
teraction with members of the Meis and pKnox families of transcription
factors, permitting selective targeting of genes regulated by Pbx-Hox
complexes. In addition, because most motifs bound by Pbx-Meis1/pKnox1
were not bound by Pbx1-Hox complexes, the leukemic potential of Meis1
in myeloid leukemias may involve shifting Pbx proteins from promoters
containing Pbx-Hox motifs to those containing Pbx-Meis motifs.