Loss of Smad3 in acute T-cell lymphoblastic leukemia

N Engl J Med. 2004 Aug 5;351(6):552-9. doi: 10.1056/NEJMoa031197.


Background: The receptors for transforming growth factor beta (TGF-beta) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates--Smad3--in the pathogenesis of lymphoid neoplasia is unknown.

Methods: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-beta and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted.

Results: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-beta on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis.

Conclusions: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.

MeSH terms

  • Adult
  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Child
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Exons
  • Gene Deletion
  • Gene Expression
  • Humans
  • Interleukin-2 / biosynthesis
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, T-Cell / genetics
  • Leukemia, T-Cell / metabolism*
  • Leukemia-Lymphoma, Adult T-Cell / genetics
  • Leukemia-Lymphoma, Adult T-Cell / metabolism*
  • Mice
  • Mice, Knockout
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Sequence Analysis, DNA
  • Signal Transduction
  • Smad3 Protein
  • T-Lymphocytes / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Interleukin-2
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • SMAD3 protein, human
  • Smad3 Protein
  • Smad3 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27