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

Ning Wang, Hyung Gyoong Kim, Claudiu V. Cotta, Mei Wan, Yi Tang, Christopher A. Klug, Xu Cao

Research output: Contribution to journalArticle

Abstract

Homeobox (Hox) gene mutations and their altered expressions are frequently linked to human leukemia. Here, we report that transforming growth factor β (TGFβ)/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 TGFβ/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 TGFβ/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.

Original languageEnglish (US)
Pages (from-to)1469-1480
Number of pages12
JournalThe EMBO journal
Volume25
Issue number7
DOIs
StatePublished - Apr 5 2006
Externally publishedYes

Fingerprint

Bone Morphogenetic Proteins
Homeobox Genes
Transforming Growth Factors
Bone
Bone Marrow
Smad4 Protein
DNA
Leukemia
Genes
Deregulation
Hematopoiesis
Transcription
Acute Myeloid Leukemia
Bone Marrow Cells
Fusion reactions
Cells
Mutation
Therapeutics

Keywords

  • Hox
  • Leukemia
  • Myeloid
  • Smad
  • TGFβ/BMP

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

TGFβ/BMP inhibits the bone marrow transformation capability of Hoxa9 by repressing its DNA-binding ability. / Wang, Ning; Kim, Hyung Gyoong; Cotta, Claudiu V.; Wan, Mei; Tang, Yi; Klug, Christopher A.; Cao, Xu.

In: The EMBO journal, Vol. 25, No. 7, 05.04.2006, p. 1469-1480.

Research output: Contribution to journalArticle

Wang, Ning ; Kim, Hyung Gyoong ; Cotta, Claudiu V. ; Wan, Mei ; Tang, Yi ; Klug, Christopher A. ; Cao, Xu. / TGFβ/BMP inhibits the bone marrow transformation capability of Hoxa9 by repressing its DNA-binding ability. In: The EMBO journal. 2006 ; Vol. 25, No. 7. pp. 1469-1480.
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