Stephan M. Tanner, Ph.D.
The Ohio State University
Abstract:
Chronic lymphocytic leukemia (CLL) is a disease with high inheritance, meaning that blood relatives face an increased risk to develop the disease, yet genetic analyses revealed no responsible disease gene so far. Partial losses of chromosomes are common events in the abnormal B-cells that cause CLL. Loss of a region in chromosome 13 occurs in >50% of all CLL cases and less frequent losses are reported in other chromosome such as 11, 17, and 6.
Our genome-wide search pointed to chromosome 9, when a segment of this chromosome cosegregated with the disease in a large family with CLL. The DAPK1 gene located in this region was downregulated due to a mutation that facilitates binding of the HOXB7 inhibitor. Moreover, in many CLL cases DAPK1 expression is downregulated due to chemical (epigenetic) modification of the DNA. Thus, we showed that downregulation of the cell death-promoting gene DAPK1 is an almost universal finding in CLL, which may explain why the CLL causing cells do not die as programmed. However, we do not yet fully understand what leads to the silencing of this gene. Thus, our research aims to determine the mechanisms involved in downregulation of DAPK1 in familial and sporadic CLL.