Germline Allele-Specific Expression of <em>DAPK1</em> in Chronic Lymphocytic Leukemia

<div><p>We previously reported a rare germline variant (c.1-6531) that resulted in allele–specific expression (ASE) of <em>death-associated protein kinase 1</em> (<em>DAPK1</em>) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of <em>DAPK1</em>. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline <em>DAPK1</em> ASE in 17 out of 120 (14.2%) CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the <em>DAPK1</em> 5′ upstream regulatory region, within distinct exons or in the 3′-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in <em>DAPK1</em> is associated with ASE. Our data indicate that ASE at the <em>DAPK1</em> gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.</p>