Although PBX proteins are known to increase DNA-binding/transcriptional activity of HOX proteins through their direct binding， the functional importance of their interaction in leukemogenesis is unclear.We recently reported that overexpression of a 4-homeobox-gene signature (ie， PBX3/HOXA7/HOXA9/HOXA11) is an independent predictor of poor survival in patients with cytogenetically abnormal acute myeloid leukemia (CA-AML). Here we show that it is PBX3， but not PBX1 or PBX2， that is consistently coexpressed with HOXA9 in various subtypes of CA-AML， particularly MLL-rearranged AML， and thus appears as a potential pathologic cofactor of HOXA9 in CA-AML. We then show that depletion of endogenous Pbx3 expr... More
Although PBX proteins are known to increase DNA-binding/transcriptional activity of HOX proteins through their direct binding， the functional importance of their interaction in leukemogenesis is unclear.We recently reported that overexpression of a 4-homeobox-gene signature (ie， PBX3/HOXA7/HOXA9/HOXA11) is an independent predictor of poor survival in patients with cytogenetically abnormal acute myeloid leukemia (CA-AML). Here we show that it is PBX3， but not PBX1 or PBX2， that is consistently coexpressed with HOXA9 in various subtypes of CA-AML， particularly MLL-rearranged AML， and thus appears as a potential pathologic cofactor of HOXA9 in CA-AML. We then show that depletion of endogenous Pbx3 expression by shRNA significantly inhibits MLL-fusion-mediated cell transformation， and coexpressed PBX3 exhibits a significantly synergistic effect with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo. Furthermore， as a proof of concept， we show that a small peptide， namely HXR9， which was developed to specifically disrupt the interactions between HOX and PBX proteins， can selectively kill leukemic cells with overexpression of HOXA/PBX3 genes. Collectively， our data suggest that PBX3 is a critical cofactor of HOXA9 in leukemogenesis， and targeting their interaction is a feasible strategy to treat presently therapy resistant CA-AML (eg， MLL-rearranged leukemia) in which HOXA/PBX3 genes are overexpressed.
