Abstract
We previously reported a rare germline variant (c.1-6531) that resulted in allele–specific expression (ASE) of death-associated protein kinase 1 (DAPK1) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline DAPK1 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 DAPK1 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 DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the Western world with an annual incidence of 4.48 per 100.000 [1]
Development and establishment of a semi highthroughput method for allele–specific expression (ASE) detection Previously, we demonstrated that both increased promoter methylation and a rare germline variant (c.1-6531A.G) at the death-associated protein kinase 1 (DAPK1) gene locus are associated with DAPK1 transcription and thereby contribute to CLL risk
We hypothesized that ASE of DAPK1 could be present in CLL patients in the absence of this particular rare genetic variant
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the Western world with an annual incidence of 4.48 per 100.000 [1]. It is characterized by late onset with a median age of 72 years at diagnosis. The CLL genome is characterized by recurrent genetic as well as epigenetic alterations [2]. Familial clustering of CLL has been described in up to 10% of cases [3,4]. Genome-wide association studies identified several susceptibility loci associated with CLL, mechanisms of increased risk in carriers are largely unknown [5,6,7]
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