ATAXIA-TELANGIECTASIA AND T-CELL LEUKEMIAS - NO EVIDENCE FOR SOMATIC ATM MUTATION IN SPORADIC T-ALL OR FOR HYPERMETHYLATION OF THE ATM-NPATE14 BIDIRECTIONAL PROMOTER IN T-PLL/

The ATM gene deficient in ataxia-telangiectasia, a recessive multisyst em disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-c ell prolymphocytic leukemia (T-PLL), which is often associated with cy togenetic aberrations of chromosome 14. The ATM gene was shown to sust ain frequent loss-of-function mutations in T-PLL tumor cells, consiste nt with functioning as a tumor suppressor gene in this leukemia, To in vestigate the possibility of nomnutational or nonrecombinational mecha nisms of T-PLL development, we have used bisulfite genomic sequencing to analyze DNA methylation in the putative bidirectional promoter regi on of the closely linked ATM and NPAT/E14 genes within the CpG island at 11q22-q23, We show that this region is completely demethylated in l ymphocytes expressing ATM; however, no extensive hypermethylation was found in 9 T-PLL tumor DNA samples without evidence of ATM/p53 mutatio ns. Because acute T-cell lymphoblastic leukemias (T-ALL) were also obs erved in ataxia-telangiectasia patients and T-ALL tumor cells contain chromosome 14 abnormalities, 19 presentation samples of T-ALL patients were analyzed for ATM mutations. Although T-ALL patients exhibited ra re nucleotide substitutions not previously found in ATM, all were iden tified in the germ-line, indicating constitutional polymorphisms, pote ntially confined to ethnic subpopulations. The absence of somatic nucl eotide changes in ATM in T-ALL as compared with T-PLL suggests a disti nct pattern of genetic events in the development of the two leukemias.