Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia.
The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in downregulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.
Agirre
Xabier
X
Foundation for Applied Medical Research, Division of Cancer, Area of Cell Therapy and Hematology Service, Clínica Universitaria, Universidad de Navarra, Pamplona, Spain.
Román-Gómez
José
J
Vázquez
Iria
I
Jiménez-Velasco
Antonio
A
Garate
Leire
L
Montiel-Duarte
Cristina
C
Artieda
Paula
P
Cordeu
Lucia
L
Lahortiga
Idoya
I
Calasanz
María José
MJ
Heiniger
Anabel
A
Torres
Antonio
A
Minna
John D
JD
Prósper
Felipe
F
D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D008840:Microfilament Proteins; D018832:Molecular Chaperones; C471711:PACRG protein, human; D011506:Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein