Mutations in the Ataxia-Telangiectasia Gene (ATM) in Patients With Chronic Lymph
Mutations in the Ataxia-Telangiectasia Gene (ATM) in Patients With Chronic Lymphocytic Leukemia
abstract & commentary
Synopsis: Molecular changes in chronic lymphocytic leukemia include mutations in p53 in about 30% of cases, and deletions in 13q, trisomy 12, and deletions in 11q in small subsets of patients. Because the gene mutated in ataxia telangiectasia (ATM) maps to 11q, Stankovic and colleagues looked at ATM protein expression and gene mutations in 32 cases. Abnormally low expression was noted in 40% of cases and mutations in the gene were noted in 18% (6 cases). Two of the six cases (one-third) with mutant genes carried germline mutations, an abnormality noted in one of 200 people in the general population. The rest of the ATM mutations were restricted to the tumor cells.
Source: Stankovic T, et al. Lancet 1999;353:26-29.
B-cell chronic lymphocytic leukemia, the most common form of leukemia in the western world, affects about 14,000 patients in the United States each year. It is a neoplasm of a particular subset of B cells, the CD5+ or B-1 subset. In general, this subset of cells responds to antigens in a T-cell-independent fashion, that is, without requiring that T cells that recognize the same antigen provide help. The B-1 subset is not completely understood, but it appears that these cells have a specialized anatomic niche (they are located in the mantle zones of normal lymphoid organs and are prevalent in the pleural and peritoneal cavity), are normally long-lived, and produce antibodies of relatively low affinity that are often specific for polysaccharide antigens found in bacterial, fungal, and parasitic pathogen cell walls. Much of the circulating IgM antibody is produced by B-1 B cells. Such antibody is often the first line of defense against an infectious organism.
Chronic lymphocytic leukemia can kill patients in several ways: the tumor cells can crowd out normal bone marrow leading to death from bone marrow failure; the immune compromise associated with the disease (perhaps added to the problems associated with the advanced age of most patients) can increase susceptibility to infectious causes of death; the disease predisposes patients to second malignant neoplasms by mechanisms that are not fully elucidated; the production of autoerythrocyte or autoplatelet antibodies either by the tumor, or more commonly, in response to the tumor, can lead to fatalities from autoimmune hemolytic anemia or thrombocytopenia; the disease can undergo histologic progression to aggressive histology lymphoma that is often refractory to treatment, a more aggressive variant of leukemia called prolymphocytic leukemia, or to acute lymphoblastic leukemia. Even with this wide variety of mechanisms by which the disease can contribute to death, 35-50% of patients die of intercurrent illness not clearly related to the leukemia.
The disease is not usually rapidly progressive and the malignant cells generally are not highly proliferative. Chronic lymphocytic leukemia is most commonly described as an accumulation of long-lived small lymphocytes and the implication is that the major cell defects propagating the malignant state are related to a failure of the cells to die when they should. The genetic lesions that have been detected in the disease are numerous; however, unlike colorectal cancer, where the defects have been ordered into a rough outline describing the sequence of events, the lesions found in chronic lymphocytic leukemia bear no clear relationship with one another. About 30% of cases have mutations involving the p53 gene on chromosome 17. About 17% of cases have trisomy involving chromosome 12. About 15% of cases have abnormalities involving the Rb gene on chromosome 13. About 13% of cases have abnormalities involving deletion of chromosome 11q. The gene or genes on chromosome 11q that are specifically involved in the pathogenesis of leukemia are not defined.
However, one candidate gene on chromosome 11q is at 11q22-23, the gene mutated in patients with ataxia-telangiectasia (ATM). Ataxia-telangiectasia is a rare autosomal recessive disorder that produces a progressive cerebellar ataxia, cutaneous telangiectasia, and a striking sensitization to DNA damaging agents such as ionizing radiation and chemotherapy agents. It is thought that ATM normally participates in the linkage of DNA damage with the pathway that elicits the death response of the cell.1 Thus, damaged cells accumulate rather than die when the gene is mutated. Interestingly, patients with ATM have an increased incidence of lymphoid neoplasms; the mechanism of susceptibility is undefined. Although homozygosity is rare, it has been estimated that about one in 200 people in the population carry a germline mutation in one ATM allele. Some evidence suggests that carriers of mutant ATM alleles may be more likely to develop breast cancer.2
In order to evaluate the role of ATM in chronic lymphocytic leukemia, Stankovic and her colleagues analyzed 32 patients. In 20 patients, they examined the expression of the ATM protein by Western blot analysis. In eight of 20 (40%), ATM protein expression was absent (in 3) or significantly decreased (in 5). In the malignant cells of most patients, the level of ATM protein was higher than in normal peripheral blood cells. Restriction endonuclease fingerprinting was done to evaluate the genotype in 32 patients and then individual genes were sequenced. Six patients (18%) had malignant cells with mutated ATM alleles, and in two of these, mutations were found in normal cells of the patient suggesting that the patient carried a germline ATM mutation. None of the eight patients with decreased levels of protein expression were found to have chromosome 11q22-23 deletions; in three, small intragenic insertions or deletions were detected and in five, missense mutations accounted for the defect. Therefore, this result implies that the gene in these cases contained mutations that affected expression rather than deletions. There was no apparent association between the presence of ATM abnormalities and tumor stage.
Commentary
The molecular pathogenesis of B-cell chronic lymphocytic leukemia remains a mystery. A role for antigen is possible. Defects in apoptosis seem likely. However, there is no understanding about how any of the observed abnormalities actually serve to promote the disease. In this study, abnormal levels of expression of the ATM protein were identified in about 40% of the cases tested and in each instance, a mutation in the gene accounted for the alteration. None of these cases demonstrated the deletions of chromosome 11q that has been described in about 13% of chronic lymphocytic leukemia cases. Thus, it is possible that a careful analysis of a larger series of patients would find an even higher prevalence of abnormalities.
Another point to be addressed by a larger series of patients is whether the presence of abnormalities in the ATM gene identify any particular clinical characteristics. It is possible that alterations in ATM expression occur over time in patients and that the emergence of this defect could be associated with a change in the clinical course. This is not entirely an idle speculation. In one prospective five-year study of 45 patients with chronic lymphocytic leukemia, Fegan and colleagues noted the development of karyotypic clonal evolution in 38% of patients and within this group with evolving genetic changes, 11q deletions were the most common newly developing abnormality.3 Of course, it is unknown whether this is ATM related.
ATM has been documented to be involved in the pathogenesis of another lymphoid tumor, T-cell prolymphocytic leukemia (T-PLL), a rare, but aggressive leukemia of small T cells. T-cell tumors occur more commonly in patients affected by ATM than do B-cell tumors and T-PLL is one of the more common T-cell tumors that occur.3 An analysis of sporadic cases of T-PLL found that 15 of 24 cases had deletions involving the ATM gene on 11q22-23 in one series4 and 10 of 15 cases had loss of heterozygosity in another.5 Thus, ATM appears to contribute to about 60-67% of cases of T-PLL.
Whether mutations affecting ATM influence the pathogenesis or natural history of chronic lymphocytic leukemia is undefined. However, at least one group has suggested that deletions in 11q identify a subset of patients with typical-appearing chronic lymphocytic leukemia who have poorer survival.6 Further evaluation is needed to see whether such patients are more or less responsive to treatment or require treatment at an earlier stage of disease.
References
1. Westphal CH, et al. Nat Genet 1997;16:397-401.
2. Vorechovsky I, et al. Cancer Res 1996;56:2726-2732.
3. Taylor AMR, et al. Blood 1996;87:423-438.
4. Stilgenbauer S, et al. Nat Med 1997;3:1155-1159.
5. Stoppa-Lyonnet D, et al. Blood 1998;91:3920-3926.
6. Neilson AR, et al. Leukemia 1997;11:1929-1932.
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