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Previous Volume 351:552-559 August 5, 2004 Number 6 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Perspective by Downing, J. R. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background The receptors for transforming growth factor (TGF-) 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- and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27^Kip1 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- on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27^Kip1 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 p27^Kip1 work synergistically to promote T-cell leukemogenesis in mice.

Source Information

From the Laboratory of Cell Regulation and Carcinogenesis (L.A.W., T.M.F., M.M., W.L.F., R.K., S.B., A.F., K.C.F., A.B.R., J.J.L.), the Pediatric Oncology Branch (D.E.C., F.M.B.), and the Genetics Branch (P.D.A.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.; and the Department of Biomedicine and Surgery, Division of Oncology, Faculty of Health Sciences, University Hospital, Linköping, Sweden (T.M.W.).

Drs. Wolfraim, Fernandez, and Mamura and Mr. Fuller contributed equally to the article.

Address reprint requests to Dr. Letterio at LCRC, CCR, NIH Bldg. 41, Rm. C629, 41 Library Dr., Bethesda, MD 20892-5055, or at letterij{at}mail.nih.gov.

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