Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia

Floriana Manodoro*, Jacek Marzec, Tracy Chaplin, Farideh Miraki-Moud, Eva Moravcsik, Jelena V. Jovanovic, Jun Wang, Sameena Iqbal, David Taussig, David Grimwade, John G. Gribben, Bryan D. Young, Silvana Debernardi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

Distinct patterns of DNA methylation characterize the epigenetic landscape of promyelocytic leukemia/retinoic acid receptor-alpha (PML-RAR alpha)-associated acute promyelocytic leukemia (APL). We previously reported that the microRNAs (miRNAs) clustered on chromosome 14q32 are overexpressed only in APL. Here, using high-throughput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differentially methylated region (DMR), which also included the site motifs for the enhancer blocking protein CCCTC-binding factor (CTCF). Comparing the profiles of diagnostic/remission paired patient samples, we show that hypermethylation was acquired in APL in a monoallelic manner. The cytosine guanine dinucleotide status of the DMR correlated with expression of the miRNAs following a characteristic position-dependent pattern. Moreover, a signature of hypermethylation was also detected in leukemic cells from an established transgenic PML-RARA APL mouse model at the orthologous region on chromosome 12, including the CTCF binding site located upstream from the mouse miRNA cluster. These results, together with the demonstration that the region does not show DNA methylation changes during myeloid differentiation, provide evidence that 14q32 hypermethylation is implicated in the pathogenesis of APL. We propose a model in which loss of imprinting at the 14q32 domain leads to overexpression of the miRNAs in APL.

Original languageEnglish
Pages (from-to)2066-2074
Number of pages9
JournalBlood
Volume123
Issue number13
DOIs
Publication statusPublished - 27 Mar 2014

Keywords

  • ACUTE MYELOID-LEUKEMIA
  • CTCF-BINDING-SITE
  • RAR-ALPHA
  • TRANSCRIPTION FACTOR
  • METHYLATION CHANGES
  • GENOMIC REGION
  • FUSION PROTEIN
  • PMLRAR-ALPHA
  • EXPRESSION
  • IGF2

Fingerprint

Dive into the research topics of 'Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia'. Together they form a unique fingerprint.

Cite this