AKAP12, a gene with tumour suppressor properties, is a target of promoter DNA methylation in childhood myeloid malignancies.
A-kinase anchor protein 12 (AKAP12) is a scaffold protein that participates in mitotic regulation and other signalling processes and probably exerts tumour suppressor function. We hypothesized that epigenetic repression of the AKAP12 gene might occur in malignant myeloid disorders. This study demonstrated that the 5' CpG island of AKAP12 was unmethylated in normal haematopoietic progenitors and granulocytes but exhibited profound methylation in Kasumi-1 and SKNO-1 leukaemic myeloblasts. Correspondingly, AKAP12 was expressed in normal progenitors but transcriptionally silent in leukaemic blasts. Re-expression of AKAP12 in Kasumi-1 and SKNO-1 cells was accomplished by treatment with MS275 alone or in combination with zebularine, indicating epigenetic mechanisms of gene repression. AKAP12 hypermethylation was found in one case of refractory anaemia with excess blasts (RAEB) and two cases of acute myeloid leukaemia (AML) in a panel of 21 blood or bone marrow samples from children with malignant myeloid disorders including refractory cytopenia, RAEB, juvenile myelomonocytic leukaemia and AML. While AKAP12 function has not been previously linked to leukaemogenesis, our results raise the possibility that epigenetic silencing of AKAP12 is involved in myeloid malignancies.
Division of Paediatric Haematology-Oncology, University of Freiburg, Freiburg, Germany. christian.flotho@uniklinik-freiburg.de
Christian
C
Flotho
Annika
A
Paulun
Christiane
C
Batz
Charlotte M
CM
Niemeyer
D054758:A Kinase Anchor Proteins; D000293:Adolescent; D000754:Anemia, Refractory, with Excess of Blasts / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics / Q000378:metabolism; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured
D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm