Development of clinical leukemia requires the acquisition of one or more additional genetic mutations after birth, and previous studies have suggested that these mutations are linked to abnormal immune responses to infection.

Researchers have sought to determine why the TEL-AML1 fusion event shows no clinical effect for more than a decade, and what properties of the TEL-AML1 protein are involved in the acquisition of secondary genetic mutations and the development of clinical leukemia.

Mel Greaves and colleagues from the Institute of Cancer Research in the United Kingdom now report in the JCI that dysregulation of a signaling pathway involving the growth factor TGF-beta is a critical component of TEM-AML1 function. TGF-beta normally regulates cell differentiation and self-renewal as well as immune and inflammatory responses. These authors show that certain mouse cells expressing TEL-AML1 proliferate at a slower rate than their parent cells, but that these cells as well as human cord blood progenitor cells expressing TEL-AML1 have a marked growth advantage in the presence of TGF-beta, compared to normal cells.

These data suggest that loss of sensitivity to TGF-beta could be an important component of the function of TEL-AML1. The precise mechanism by which TEL-AML1 inhibits TGF-beta signaling is not yet clear, but the results of this study indicate that it involves TEL-AML1 binding to the TGF-beta target molecule Smad3.

Further studies will be required to determine how cells expressing TEL-AML1 may be further selected by immune or inflammatory reactions.

Note: If no author is given, the source is cited instead.

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