Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation

The p73 gene is located on 1p36.2-3, a region that is frequently deleted in human cancer. Because p73 encodes for a protein that is both structurally and functionally homologous to the p53 protein, p73 has been postulated to be a candidate tumor suppressor gene. To date, however, mutations of p73 ha ve not been found. To study methylation of the p73 5'CpG island, a human ba cterial artificial chromosome clone containing exon 1 and the 5' region of p73 was isolated. There was no evidence for p73 exon 1 methylation in norma l tissues. In contrast, p73 was aberrantly methylated in approximately 30% of primary acute lymphoblastic leukemias (ALLs) and Burkitt's lymphomas. Th ere was no evidence for methylation in any other types of hematological mal ignancies or solid tumors examined. In both leukemia cell lines and primary ALLs, methylation was associated with transcriptional loss of p73 by rever se transcription-PCR, mie used single-strand conformational polymorphisms t o screen fur paint mutations in a series of primary ALLs and found no mutat ions leading to a change in protein structure. Our results show that methyl ation of p73 is a frequent event in specific types of hematological maligna ncies and suggest that epigenetic silencing of p73 could have important con sequences for cell-cycle regulation.