BIALLELIC MUTATIONS IN THE ATM GENE IN T-PROLYMPHOCYTIC LEUKEMIA

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characte rized by cerebellar ataxia, oculocutaneous telangiectasia, immune defi ciency, genome instability and predisposition to malignancies, particu larly T-cel[ neoplasms(1-3). The responsible gene, designated ataxia-t elongiectasia mutated(ATM), was recently identified by positional clon ing in the chromosomal region 11q22.3-23.1 (ref. 4, 5) ATM is 150 kb i n length, consists of 66 exons and encodes a nuclear phosphoprotein of approximately 350 kDa (ref. 4-9). Although ATM is considered to be a tumorigenic factor in several human cancers, it has not yet been found mutated in tumors of non-AT patients. Given the marked predisposition of AT patients to develop neoplasms of the T-cell lineage(3), we anal yzed a series of T-cell leukemias (T-prolymphocytic leukemia, or T-PLL ) in non-AT patients in search of genomic changes associated with the development of this disease. Among the recurrent aberrations identifie d, deletion of the chromosome arm 11q was very frequent. Subsequent mo lecular cytogenetic analyses allowed us to define a small commonly del eted segment at 11q22.3-23.1 in 15 of 24 T-PLLs studied. Since this cr itical region contained ATM, we further analyzed the remaining copy of the gene in six cases showing deletions affecting one ATM allele. In all six cases, mutations of the second ATM allele were identified, lea ding to the absence, premature truncation or alteration of the ATM gen e product. Thus, our study demonstrates disruption of both ATM alleles by deletion or point mutation in T-PLL, suggesting that ATM functions as a tumor-suppressor gene in tumors of non-AT individuals.