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  • The EMBO Journal (2006) 25, 1469 - 1480
  • doi:10.1038/sj.emboj.7601037

Published online: 9 March 2006

TGFbold beta/BMP inhibits the bone marrow transformation capability of Hoxa9 by repressing its DNA-binding ability

Ning Wang1,2, Hyung-Gyoong Kim3, Claudiu V Cotta1,3, Mei Wan1, Yi Tang1, Christopher A Klug3 and Xu Cao1,2

  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
  2. Department of Pharmacology, University of Alabama at Birmingham, Birmingham, AL, USA
  3. Department of Microbiology, Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence to:

Xu Cao, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Tel.: +1 205 934 0162; Fax: +1 205 934 1775; E-mail: cao@path.uab.edu

Received 7 September 2005; Accepted 14 February 2006

Homeobox (Hox) gene mutations and their altered expressions are frequently linked to human leukemia. Here, we report that transforming growth factor beta (TGFbeta)/bone morphogenetic protein (BMP) inhibits the bone marrow transformation capability of Hoxa9 and Nup98-Hoxa9, the chimeric fusion form of Hoxa9 identified in human acute myeloid leukemia (AML), through Smad4, the common Smad (Co-Smad) in the TGFbeta/BMP signaling pathway. Smad4 interacts directly with the homeodomain of Hoxa9 and blocks the ability of Nup98-Hoxa9 to bind DNA, thereby suppressing its ability to regulate downstream gene transcription. Mapping data revealed that the amino-terminus of Smad4 mediates this interaction and overexpression of the Hoxa9 interaction domain of Smad4 was sufficient to inhibit the enhanced serial replating ability of primary bone marrow cells induced by Nup98-Hoxa9. These studies establish a novel mechanism by which TGFbeta/BMP regulates hematopoiesis and suggest that modification of Hox DNA-binding activity may serve as a novel therapeutic intervention for those leukemias that involve deregulation of Hox.

  • Keywords:

    • Hox,
    • leukemia,
    • myeloid,
    • Smad,
    • TGFbeta/BMP