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.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Roman-Gomez
Jose
J
Hematology Department, Reina Sofia Hospital, Avda, Menendez Pidal s/n, 14004 Cordoba, Spain. peperosa@teleline.es
Castillejo
Juan A
JA
Jimenez
Antonio
A
Cervantes
Francisco
F
Boque
Concepcion
C
Hermosin
Lourdes
L
Leon
Angel
A
Grañena
Albert
A
Colomer
Dolors
D
Heiniger
Anabel
A
Torres
Antonio
A
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis
D000970:Antineoplastic Agents; D015820:Cadherins; C099972:H-cadherin; D016898:Interferon-alpha; D012333:RNA, Messenger; D002118:Calcium