Characterize the Major Types of Hematological Malignancies1

In hematological malignancies, homozygous deletion of @/6â@NK4A is primarily limited to ALL3 and non-Hodgkin's lymphoma (10—13). Although ALL has among the highest reported rates of homozygous deletion at 9p2l in primary neoplasia (6, 9—1, 14), assigning a tumor suppressor role to p16@―@4― alone in these malignancies is difficult, because most cases include both p15@―4'@and p16@―4― in the deleted region (15). A subset of malignancies, including ALL, have selective homozygous deletion of @ (16, 17), but these malignancies generally represent only a minority of those with homozygous dele tion. Our recent findings demonstrate that inactivation of p15―@―4'@ and p/6@―4@is a much more frequent event in neoplasia than indicated solely by the presence of homozygous deletions. We and others have observed that aberrant methylation of 5' region CpG islands in these genes represents an alternative mechanism to homozygous deletion and coding region mutations for inactivation (18—22).For each gene, this hypermethylation is found in neoplastic cells and is associated with transcriptional loss that was reversed by treatment with the DNA-demethylating agent 5-aza-2'-deoxycytidine (18—20,22). Un like homozygous deletions, inactivation of these genes through pro moter region hypermethylation is selective, typically limited to only