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Mar 17, 2009

Malfunction in Immune Response Pathway Is Key to How a Fused Gene Promotes Childhood Leukemia

  • An error in a signaling pathway involving the growth factor TGF-ß is a critical component of the TEM-AML1 fusion gene, an abnormality in childhood acute lymphoblastic leukemia, reports investigators from the Institute of Cancer Research in the U.K.

    TEL-AML1 fusion usually occurs before birth but can remain clinically silent for up to 15 years. Development of clinical leukemia requires the acquisition of one or more additional genetic mutations after birth. Previous studies have suggested that these mutations are linked to abnormal immune responses to infection.

    TGF-ß normally regulates cell differentiation and self-renewal as well as immune and inflammatory responses. In the current study, the scientists found loss of sensitivity to TGF-ß. Though precisely how TEL-AML1 inhibits TGF-ß signaling is not yet clear, it involves TEL-AML1 binding to the TGF-ß target molecule Smad3, compromising its ability to activate target promoters, they note.

    The researchers demonstrated that a particular mouse cells expressing TEL-AML1 proliferate at a slower rate than their parent cells. These cells and human cord blood progenitor cells expressing TEL-AML1, however, had a marked growth advantage in the presence of TGF-ß compared to normal cells.

    This may provide a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1–expressing preleukemic clones.

    The article appeared onlined March 16 in the Journal of Clinical Investigation.

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