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Lack of CpG Island Methylator Phenotype Defines a Clinical Subtype of T-Cell Acute Lymphoblastic Leukemia Associated With Good Prognosis

From the Hematology Department, Reina Sofia Hospital, Cordoba; Hematology Department, Carlos Haya Hospital, Malaga; and Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain

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

PURPOSE: To examine cancer genes undergoing epigenetic inactivation in a set of T-cell acute lymphoblastic leukemias (T-ALLs) to obtain the CpG island methylator phenotype (CIMP) in the disease and its possible correlation with clinical features and outcome of the patients.

PATIENTS AND METHODS: Methylation-specific polymerase chain reaction was used to analyze methylation of the ADAMTS-1, ADAMTS-5, APAF-1, ASPP-1, CDH1, CDH13, DAPK, DIABLO, DKK-3, LATS-1, LATS-2, NES-1, p14, p15, p16, p57, p73, PARK-2, PTEN, sFRP1/2/4/5, SHP-1, SYK, TMS-1, and WIF-1 genes in samples from 50 consecutive T-ALL patients (19 children and 31 adults). Results were compared with results obtained in 286 B-cell acute lymphoblastic leukemias (B-ALLs).

RESULTS: A total of 88% of the T-ALL samples had at least one gene methylated. According to the number of methylated genes observed in each individual sample, 12 patients (24%) were included in the CIMP– group (zero to two methylated genes), and 38 patients (76%) were included in the CIMP+ group (> two methylated genes). Clinical features and remission rate did not differ significantly among both groups of patients. Estimated disease-free survival (DFS) rate at 12 years and overall survival (OS) rate at 13 years were 100% and 91% for the CIMP– group and 20% and 17% for the CIMP+ group, respectively (P = .0006 and P = .003, respectively). Multivariate analysis demonstrated that methylation profile was an independent prognostic factor in predicting DFS (P = .05) and OS (P = .02). A group of five genes (SYK-1, ASPP-1, sFRP-2, sFRP-5, and WIF-1) showed specificity for T-ALL compared with B-ALL.

CONCLUSION: Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in T-ALL.

Supported by Grants No. 03/0141, 01/0013-01, 01/F018, and 02/1299 from Fondo de Investigacion Sanitaria (Spain); Navarra Government (grant No. 31/2002); RETIC Grant No. C03/10; Junta de Andalucia Grants No. 03/143 and 03/144; and funds from IMABIS (Malaga, Spain), "UTE project CIMA," Fundación de Investigación Médica Mutua Madrileña Automovilista, and Asociacion Medicina e Investigacion.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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