DEFICIENCY OF THE ATM PROTEIN EXPRESSION DEFINES AN AGGRESSIVE SUBGROUP OF B-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA

The gene mutated in ataxia telangiectasia, ATM, on human chromosome 11 q22-q23 is implicated in cell cycle control and DNA repair. Ataxia tel angiectasia patients as well as ATM-deficient mice are immune deficien t and develop lymphoproliferative disease. Abnormalities in 11q22.3-q2 3.1 have also been described in B-cell chronic lymphocytic leukemia (B -CLL), We analyzed B-CLL samples for loss of heterozygosity (LOH) usin g microsatellite markers located at the ATM (D11S2179), mixed-lineage leukemia (MLL; D11S1356), and BCL1 (D11S987) loci, all of which are lo cated around 11q23, Five (14%) of 36 informative cases showed LOH at t he ATM gene, and two of these five cases had LOH at the MLL gene. No L OH was detected at the BCL1 locus, and none of the cases showed LOH at the MLL gene without LOH at the ATM gene, Four of these five cases wi th LOH at the ATM gene were studied for ATM protein expression by West ern blot analysis. All four cases lacked ATM protein. An additional 11 1 cases of B-CLL were studied for expression of ATM protein by Western blot analysis and RTA. Thirty-eight (34%) of these cases showed ATM l evels <50% of that seen in normal lymphoid cells. No morphological or immunophenotypic difference was observed between ATM-deficient B-CLL c ases and cases with normal ATM expression. However, patients with ATM deficiency had significantly shorter survival times (35.66 versus 97.3 months; P = 0.003) and more aggressive disease, suggesting that ATM i s involved in the leukemogenesis of B-CLL, These data also suggest tha t the ATM gene may play a role in the reported 11q23 abnormality in B- CLL, which also characterizes an aggressive disease.