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

TY - JOUR

T1 - Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia

AU - Manodoro, Floriana

AU - Marzec, Jacek

AU - Chaplin, Tracy

AU - Miraki-Moud, Farideh

AU - Moravcsik, Eva

AU - Jovanovic, Jelena V.

AU - Wang, Jun

AU - Iqbal, Sameena

AU - Taussig, David

AU - Grimwade, David

AU - Gribben, John G.

AU - Young, Bryan D.

AU - Debernardi, Silvana

PY - 2014/3/27

Y1 - 2014/3/27

N2 - 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.

AB - 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.

KW - ACUTE MYELOID-LEUKEMIA

KW - CTCF-BINDING-SITE

KW - RAR-ALPHA

KW - TRANSCRIPTION FACTOR

KW - METHYLATION CHANGES

KW - GENOMIC REGION

KW - FUSION PROTEIN

KW - PMLRAR-ALPHA

KW - EXPRESSION

KW - IGF2

U2 - 10.1182/blood-2012-12-469833

DO - 10.1182/blood-2012-12-469833

M3 - Article

SN - 0006-4971

VL - 123

SP - 2066

EP - 2074

JO - Blood

JF - Blood

IS - 13

ER -