PBX3 is an important cofactor of HOXA9 in leukemogenesis

Zejuan Li, Zhiyu Zhang, Yuanyuan Li, Stephen Arnovitz, Ping Chen, Hao Huang, Xi Jiang, Gia Ming Hong, Rejani B. Kunjamma, Haomin Ren, Chunjiang He, Chong Zhi Wang, Abdel G. Elkahloun, Peter J.M. Valk, Konstanze Döhner, Mary Beth Neilly, Lars Bullinger, Ruud Delwel, Bob Löwenberg, Paul P. LiuRichard Morgan, Janet D. Rowley, Chun Su Yuan, Jianjun Chen

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1422-1431
Number of pages10
JournalBlood
Volume121
Issue number8
DOIs
StatePublished - Feb 21 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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