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Cadherin-13, a Mediator of Calcium-Dependent Cell-Cell Adhesion, Is Silenced by Methylation in Chronic Myeloid Leukemia and Correlates With Pretreatment Risk Profile and Cytogenetic Response to Interferon Alfa

Jose Roman-Gomez, Juan A. Castillejo, Antonio Jimenez, Francisco Cervantes, Concepcion Boque, Lourdes Hermosin, Angel Leon, Albert Grañena, Dolors Colomer, Anabel Heiniger, Antonio Torres

From the Hematology Department, Reina Sofia Hospital, Cordoba; Hematology Department, Carlos Haya Hospital, Malaga; Hematology Department, Hospital Clinic; and Institut Catala d’Oncologia, Barcelona; and Hematology Department, General Hospital, Jerez, Spain.

Address reprint requests to Jose Roman-Gomez, MD, Hematology Department, Reina Sofia Hospital, Avda, Menendez Pidal s/n, 14004 Cordoba, Spain; email: peperosa{at}teleline.es.

Purpose: Cadherin-13 (CDH13) is a newly characterized cadherin molecule responsible for selective cell recognition and adhesion, the expression of which is decreased by methylation in a variety of human cancers, indicating that the CDH13 gene functions as a tumor suppressor gene. Although defective progenitor-stromal adhesion is a well-recognized feature of chronic myeloid leukemia (CML), the role of CDH13 abnormalities has not been evaluated in this disease.

Patients and Methods: We examined the methylation status of the CDH13 promoter in 179 chronic phase (CP)-CML patients and in 52 advanced-phase samples and correlated it with mRNA expression using methylation-specific polymerase chain reaction (PCR) and reverse transcriptase PCR.

Results: Aberrant de novo methylation of the CDH13 promoter region was observed in 99 (55%) of 179 of CP-CML patients, and 90 of the patients failed to express CDH13 mRNA (P < .0001). Advanced-stage samples (n = 52) showed concordant methylation results with their corresponding CP tumors, indicating that CDH13 methylation was not acquired during the course of the disease. Nevertheless, absence of CDH13 expression was more frequently observed among Sokal high-risk patients (P = .01) and was also independently associated with a shorter median progression-free survival time (P = .03) and poor cytogenetic response to interferon alfa treatment (P = .0001).

Conclusion: Our data indicate that the silencing of CDH13 expression by aberrant promoter methylation occurs at an early stage in CML pathogenesis and probably influences the clinical behavior of the disease.

Supported by grant nos. 01/0662, 99/0103, and 02/1299 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Spanish Ministry of Health.

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