Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia.

Authors: Wilhelm, Thomas  Lipka, Daniel B  Witte, Tania  Wierzbinska, Justyna A  Fluhr, Silvia  Helf, Monika  Mücke, Oliver  Claus, Rainer  Konermann, Carolin  Nöllke, Peter  Niemeyer, Charlotte M  Flotho, Christian  Plass, Christoph 
Citation: Wilhelm T, etal., Epigenetics. 2016;11(2):110-9. doi: 10.1080/15592294.2016.1145327. Epub 2016 Feb 18.
Pubmed: (View Article at PubMed) PMID:26891149
DOI: Full-text: DOI:10.1080/15592294.2016.1145327

A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative high-resolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., α, β, and γ) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The AKAP12α promoter shows DNA hypermethylation in JMML samples, which is associated with decreased AKAP12α expression. Promoter methylation of AKAP12α correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. In silico screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the AKAP12α promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of AKAP12 promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the AKAP12 promoter in JMML. Exposure to DNMT- and HDAC-inhibitors reactivates AKAP12α expression in vitro, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of AKAP12α in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.

Annotation

Disease Annotations
Objects Annotated
Objects referenced in this article

Additional Information

 
CRRD Object Information
CRRD ID: 14348967
Created: 2019-02-05
Species: All species
Last Modified: 2019-02-05
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.