Transforming growth factor-beta signaling in normal and malignant hematopoiesis

Leukemia. 2003 Sep;17(9):1731-7. doi: 10.1038/sj.leu.2403069.


Transforming growth factor-beta (TGF-beta) is perhaps the most potent endogenous negative regulator of hematopoiesis. The intracellular signaling events mediating the effects of TGF-beta are multiple, involving extensive crosstalk between Smad-dependent and MAP-kinase-dependent pathways. We are only beginning to understand the importance of the balance between these cascades as a determinant of the response to TGF-beta, and have yet to determine the roles that disruption in TGF-beta signaling pathways might play in leukemogenesis. This review summarizes current knowledge regarding the function of TGF-beta in normal and malignant hematopoiesis. The principal observations made by gene targeting studies in mice are reviewed, with an emphasis on how a disruption of this pathway in vivo can affect blood cell development and immune homeostasis. We overview genetic alterations that lead to impaired TGF-beta signaling in hematopoietic neoplasms, including the suppression of Smad-dependent transcriptional responses by oncoproteins such as Tax and Evi-1, and fusion proteins such as AML1/ETO. We also consider mutations in genes encoding components of the core cell cycle machinery, such as p27(Kip1) and p15(INK4A), and emphasize their impact on the ability of TGF-beta to induce G1 arrest. The implications of these observations are discussed, and opinions regarding important directions for future research on TGF-beta in hematopoiesis are provided.

Publication types

  • Review

MeSH terms

  • Animals
  • Hematopoiesis / physiology*
  • Humans
  • Leukemia / metabolism*
  • Mice
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / physiology*


  • Trans-Activators
  • Transforming Growth Factor beta