title: Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance.
abstract: PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B-cell (81.9%) and T-cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation-mediated inactivation of PCDH10 were less sensitive to commonly used leukemia-specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid-lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Gopeshwar
authors.initials: G
authors.lastname: Narayan
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Freddy
authors.forename: Dongxu
authors.initials: D
authors.lastname: Xie
authors.forename: Hema
authors.initials: H
authors.lastname: Liyanage
authors.forename: Lorraine
authors.initials: L
authors.lastname: Clark
authors.forename: Sergey
authors.initials: S
authors.lastname: Kisselev
authors.forename: Ji
authors.initials: J
authors.lastname: Un Kang
authors.forename: Subhadra V
authors.initials: SV
authors.lastname: Nandula
authors.forename: Catherine
authors.initials: C
authors.lastname: McGuinn
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Subramaniyam
authors.forename: Bachir
authors.initials: B
authors.lastname: Alobeid
authors.forename: Prakash
authors.initials: P
authors.lastname: Satwani
authors.forename: David
authors.initials: D
authors.lastname: Savage
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000091363:Protocadherins; D013601:T-Lymphocytes / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D015820:Cadherins; C438603:PCDH10 protein, human; D000091363:Protocadherins; D025521:Tumor Suppressor Proteins