ABSTRACT
BACKGROUND: The delta-like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3(MEG3) locus (DLK1-MEG3 locus) plays a critical role in the maintenance and differentiation of hematopoietic stem cells. Accumulating evidence implicates the imprinted genes from this locus, DLK1 and MEG3, in the development and progression of acute myeloid leukemia (AML). However, the contribution of this locus to the treatment response of patients and their survival is unknown. METHODS: DNA methylation of select CG dinucleotide-containing amplicons (CpG sites) within the DLK1-MEG3 locus and within differentially methylated regions of other imprinted loci was assessed in the mononuclear cells of 45 AML patients by combined bisulfite restriction analysis. Methylation results were compared with patient response to first-round induction therapy and overall survival. Multivariable analysis was employed to identify independent prognostic factors for patient overall survival in AML. RESULTS: Increased methylation at CpG sites within the MEG3 promotor region was observed in AML patients having longer overall survival. In addition, patients with shorter overall survival had increased expression of DLK1 and MEG3, and methylation at the MEG3-DMR CpG site inversely correlated with MEG3 expression. Multivariable analysis revealed that methylation at CG9, a non-imprinted CpG site within the MEG3 promotor region which contains a CCCTC-binding factor (CTCF)-binding DNA sequence, is an independent prognostic factor for the overall survival of AML patients. CONCLUSIONS: The results of our pilot study underscore the importance of the DLK1-MEG3 locus in AML development and progression. We identify CG9 methylation as an independent prognostic factor for AML patient survival, which suggests that distinct miRNA signatures from the DLK1-MEG3 locus could reflect varying degrees of cell stemness and present novel opportunities for personalized therapies in the future. These data provide a foundation for future studies into the role of higher-order chromatin structure at DLK1-MEG3 in AML.
Subject(s)
Calcium-Binding Proteins/genetics , DNA Methylation , Leukemia, Myeloid, Acute/drug therapy , Membrane Proteins/genetics , RNA, Long Noncoding/genetics , Adult , Female , Gene Expression Regulation, Neoplastic , Genomic Imprinting , Humans , Induction Chemotherapy , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Pilot Projects , Promoter Regions, Genetic , Sequence Analysis, DNA , Survival Analysis , Young AdultABSTRACT
Acquired von Willebrand syndrome (AVWS) is an acquired bleeding disorder with clinical and laboratory features similar to those of the inherited form of the disease. AVWS is reported in many disorders, most frequently in myeloproliferative neoplasms and in, among others, essential thrombocythemia (ET). Interestingly, ET is associated with both the thrombotic and haemorrhagic complications, which occur in 20 % and 5-30 % of patients, respectively. The present report concerns a 38-year-old man, suffering from ET, who presented with two episodes of post-arthroscopic joint bleeding after synovectomy required for the treatment of synovial hypertrophy and chronic left knee joint synovitis. We discuss the current diagnostic approaches, as well as the risk factors predisposing to bleeding and its management, in patients with essential thrombocythemia.
