Characterization of death associated protein kinase 1 (DAPK1) in B-cells

Chronic lymphocytic leukemia (CLL) is characterized by a defect in apoptotic signaling, however the molecular basis is poorly understood. Recently, we identified death associated protein kinase 1 (DAPK1), a positive mediator of apoptosis, as a novel tumor suppressor gene in CLL. A rare predisposing mutation was identified in a large CLL family. The mutation is located in a suppressor element located in the regulatory region of DAPK1, and creates an enhanced HOXB7 binding site. HOXB7 binding leads to reduced DAPK1 expression. Analysis of gene expression and DNA-methylation indicated that DAPK1 is silenced in almost all sporadic and familial cases of CLL.

The hypothesis we will test in this proposed project is that deregulation of the DAPK1-pathway in B cells is a crucial event in the pathogenesis of CLL and involves epigenetic mechanisms. In aim 1, we propose experiments to delineate the frequency of DAPK1 deregulation in CLL samples (both sporadic and familial). In aim 2 we will identify novel members of the DAPK1-pathway, which is currently unknown in B cells.

Links

• Raval et al., Cell 2007
• Claus et al., Int. J. Cancer 2012