Stephan M. Tanner, Ph.D. The Ohio State University

GENETICS

Genetic and epigenetic pathways in CLL

Update:

Chronic lymphocytic leukemia (CLL) is a disease with high inheritance, meaning that blood relatives face an increased risk to develop the disease, yet the responsible gene has not been identified. Our genome-wide search pointed to the DAPK1 gene that was downregulated in many CLL cases, which is found almost universally in CLL. This may explain why the CLL causing cells do not die as programmed. However, our first hypothesis of how this downregulation was caused turned out to apply to very few cases and we quickly decided to test an alternative hypothesis that could explain the silencing of this gene more generally. In fact, we have successfully used this idea in colorectal cancer (CRC), showing that lower expressed variants of the TGFBR1 gene makes people almost 9 times more susceptible to CRC (Valle et al 2008 SCIENCE).

We now have preliminary evidence that lower expressed variants of DAPK1 are found at greater frequency in CLL and we therefore refocused our project to 1) investigate to what extent this mechanism could explain the incidence of CLL and 2) what causes these variants to be expressed at lower levels. We remain determined to elucidate the mechanisms involved in downregulation of DAPK1 in familial and sporadic CLL.