Sunday, February 06, 2011

LEF1: the Wnt pathway in CLL

A paper from Neil Kay's group at the Mayo looks at LEF-1 which I mentioned in the last article as being part of the canonical Wnt signaling pathway.

LEF1 stands for lymphoid enhancer binding factor 1. They had previously identified aberrant expression of LEF1 in CLL. In this paper they have analyzed the canonical Wnt pathway by gene expression profiling. Whereas the pathway is inactive in normal peripheral B cells it is constitutively activated in both CLL and monoclonal B cell lymphocytosis. This suggests a role for the Wnt pathway in early CLL leukemogenesis. They also found that knockdown of LEF1 by siRNA decreases the survival of CLL cells.

TCF4, which codes for a downstream target of the Wnt pathway is overexpressed in CLL as is another Wnt target gene, CCND2. IGFBP4 protein, a Wnt inhibitor, is also overexpressed in CLL.

An important observation of this study was that LEF1 was not upregulated in activated B cells, though it was in CLL cells of both the mutated and unmutated subsets - demonstrating that it is not simply an activation marker.

Although the precise manner that the Wnt pathway is affected in CLL is not yet clear, it does provide fopr a potential target for CLL treatment. In one case though LEF1 knockdown had no effect on survival; this case had 17p deletion, suggesting that Wnt becomes irrelevant in these cases.

Notch and VEGF pathways are abnormal in CLL and these are known to interact with Wnt signaling.

Finally there is a speculation that the LEF/TCF repressor, VentX, might be lacking in CLL cells.

No comments: