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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 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

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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