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Transcriptional Silencing of the p73 Gene in Acute Lymphoblastic Leukemia and Burkitt’s Lymphoma Is Associated with 5' CpG Island Methylation¹

The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [P. G. C., M. E., S. B. B., J. G. H.]; Academic Medical Center, Department of Human Genetics-M1, 1105 AZ Amsterdam, the Netherlands [M. M. v. N.]; and Pediatric Hematology and Oncology, Rainbow Babies and Children’s Hospital [S. J. K., N. C.], and the Department of Human Genetics [S. J. K.], Case Western Reserve University, Cleveland, Ohio 44106

he 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 have not been found. To study methylation of the p73 5'CpG island, a human bacterial artificial chromosome clone containing exon 1 and the 5' region of p73 was isolated. There was no evidence for p73 exon 1 methylation in normal tissues. In contrast, p73 was aberrantly methylated in approximately 30% of primary acute lymphoblastic leukemias (ALLs) and Burkitt’s lymphomas. There was no evidence for methylation in any other types of hematological malignancies or solid tumors examined. In both leukemia cell lines and primary ALLs, methylation was associated with transcriptional loss of p73 by reverse transcription-PCR. We used single-strand conformational polymorphisms to screen for point mutations in a series of primary ALLs and found no mutations leading to a change in protein structure. Our results show that methylation of p73 is a frequent event in specific types of hematological malignancies and suggest that epigenetic silencing of p73 could have important consequences for cell-cycle regulation.

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