ATM gene deletion in patients with adult acute lymphoblastic leukemia

BACKGROUND, Loss of heterozygosity (LOH) at the ATM gene (mutated in ataxia telangiectasia [AT] patients) and ATM protein deficiency occur in 14% and 34%, respectively, of patients with chronic lymphocytic leukemia (CLL). ATM protein deficiency also is associated with aggressive disease and worse pa tient survival. Considering the aberrations in the ATM gene in CLL and the high rate of incidence of lymphoid neoplasias in AT patients, the authors i nvestigated its incidence rate and significance in patients with adult acut e lymphoblastic leukemia (ALL). METHODS. Samples from 36 adults with ALL were analyzed for LOH and homozygo us deletion (HD) using a panel of three microsatellite markers located at t he ATM gene (D11S2179), the MLL gene (D11S1356), and the BCL1 gene (D11S987 ) loci. These markers are located within the 11q13-q23 locus. RESULTS. Of the 36 informative cases, 10 (28%) showed deletions (7 LOH and 3 HDs) at the D11S2179 marker. In two patients, the deletions were extended to the MLL gene locus. These deletions were submicroscopic because only 3% (1 of 36) of patients showed abnormalities involving 11q23 using cytogenet ic studies. The authors also estimated the levels of ATM protein in 15 ALL patients and 12 healthy Volunteers by radioimmunoassay. The ATM protein lev els in cases with LOH at the ATM gene were between 15-50% of those from nor mal bone marrow. In contrast to CLL patients, patients with LOH or HD at th e ATM gene locus showed better survival compared with patients without ATM gene deletions (P = 0.003). CONCLUSIONS. LOH of the ATM gene and protein deficiency are common in adult ALL, are not demonstrated at the cytogenetic level, and are associated wit h a favorable prognosis. The authors speculate that ATM deficiency may incr ease the sensitivity of leukemic blasts to the chemotherapy used during ind uction and after disease remission in patients with adult All. The relative ly high frequency of deletion of the D11S2179 marker compared with the D11S 1356 marker suggests that ATM is the target gene of the deletion at the 11q 23 locus, and that such deletions may play a role in the pathogenesis of Al l. (C) 2000 American Cancer Society.