Hypermethylation of E-cadherin in Leukemia

E-cadherin gene is often termed a "metastasis suppressor" gene because the E-cadherin protein can suppress tumor cell invasion and metastasis. Inactivation of the E-cadherin gene occurs in undifferentiated solid tumors by both genetic and epigenetic mechanisms; however, the role of E-cadherin in hematologic malignancies is only now being recognized. E-cadherin expression is essential for erythroblast and normoblast maturation, yet expression is reduced or absent in leukemic blast cells. This study examined the messenger RNA (mRNA) and protein expression of the E-cadherin gene in bone marrow and blood samples from normal donors and patients with leukemia. We found that all normal donor samples expressed E-cadherin mRNA, whereas both samples of acute myelogenous leukemia and chronic lymphocytic leukemia had a significant reduction or absence of expression. However, normal blast counterparts expressed only a low level of E-cadherin surface protein. Sodium bisulphite genomic sequencing was used to fully characterize the methylation patterns of the CpG island associated with the E-cadherin gene promoter in those samples with matched DNA. All of the normal control samples were essentially unmethylated; however, 14 of 18 (78%) of the leukemia samples had abnormal hypermethylation of the E-cadherin CpG island. In fact both alleles of the E-cadherin gene were often hypermethylated. We conclude the E-cadherin gene is a common target for hypermethylation in hematologic malignancies.