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Loss of Smad3 in acute T-cell lymphoblastic leukemia
Lawrence A Wolfraim1, Tania M Fernandez, Mizuko Mamura
1Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md, USA.
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.
Insights
Loss of Smad3 protein is specific to pediatric T-cell acute lymphoblastic leukemia (ALL). Reduced Smad3 expression and p27Kip1 loss synergistically promote T-cell leukemogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Transforming growth factor beta (TGF-beta) receptors and signaling intermediates are crucial tumor suppressors.
- The specific role of Smad3 in lymphoid neoplasia pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of Smad3 in pediatric acute leukemia, particularly T-cell acute lymphoblastic leukemia (ALL).
- To examine the impact of Smad3 deficiency on T-cell response to TGF-beta and leukemogenesis.
Main Methods:
- Smad3 mRNA and protein levels were measured in leukemia cells from 19 children.
- The SMAD3 gene (MADH3) was sequenced in T-cell ALL samples.
- Smad3 function was assessed in mice with Smad3 or p27Kip1 gene inactivation.
Main Results:
- Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and acute nonlymphoblastic leukemia (ANLL).
- No SMAD3 gene mutations were detected in T-cell ALL; Smad3 mRNA levels were similar to normal T cells.
- Loss of Smad3 impaired TGF-beta's inhibitory effect on T-cell proliferation and promoted T-cell leukemogenesis in mice, especially when combined with p27Kip1 loss.
Conclusions:
- Absence of Smad3 protein is a distinguishing characteristic of pediatric T-cell ALL.
- Synergistic action between reduced Smad3 expression and p27Kip1 loss contributes to T-cell leukemogenesis.
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