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Promoter Methylation-Mediated Inactivation of PCDH10 in Acute Lymphoblastic Leukemia Contributes to Chemotherapy Resistance

Narayan, Gopeshwar; Freddy, Allen J.; Xie, Dongxu; Liyanage, Hema; Clark, Lorraine N.; Kisselev, Sergey; Kang, Ji Un; Nandula, Subhadra; McGuinn, Catherine; Subramaniyam, Shivakumar; Alobeid, Bachir; Satwani, Prakash; Savage, David G.; Vundavalli, Murty V.

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 investi- gated 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 hypermethyl- ation 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 1⁄4 4) and leukemia cell lines (N 1⁄4 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyl- transferases. 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-line- age leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epige- netic therapy.

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Title
Genes, Chromosomes & Cancer
DOI
https://doi.org/10.1002/gcc.20922

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