INACTIVATION OF THE ATM GENE IN T-CELL PROLYMPHOCYTIC LEUKEMIAS

T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature leukem ia that occurs both in adults as a sporadic disease and in younger pat ients suffering an hereditary condition, ataxia telangiectasia (AT). T he ATM gene, located in the 11q22-23 chromosomal region, is consistent ly mutated in AT patients. The strong predisposition of AT patients to develop T-PLL and the high frequency of T-cell leukemias/lymphomas ob served in atm-deficient mice, together with the known functions of the ATRS protein, led us to evaluate the ATM gene as a potential tumor su ppressor gene involved in T-PLL. Paired leukemic and nonleukemic cells were obtained from a series of 15 patients suffering sporadic T-PLLs, allowing loss of heterozygosity (LOH) analysis. LOH of the 11q22-23 r egion was detected in 10 of these 15 cases (67%). The minimal deleted region was defined as an approximately 2.5 Mb interval that contained the ATM gene. No ATM rearrangement or biallelic deletion was detected by Southern blotting in the T-PLL series. However, in five T-PLLs with LOH of the 11q22-23 region, Western blot analysis showed either undet ectable (3 cases) or decreased levels (1 case) of ATM protein, whereas ATM was present at high levels in cases without LOH, The protein trun cation test (PTT) was then used to search for mutations in the ATM gen e. Four mutations (1 nonsense, 2 aberrant splicings, and 1 missense) w ere detected in patients with LOH and none in patients without LOH of the region. The acquired character of these ATM mutations was demonstr ated in three patients. Altogether, allelic ATM inactivations by large deletions or mutations were found in approximately two thirds of T-PL L. ATM is thus a tumor suppressor gene whose inactivation is a key eve nt in the development of T-cell prolymphocytic leukemias. (C) 1998 by The American Society of Hematology.