Nearly a fifth (18%) of patients with CLL have leukemia cells with deletions in the long arm of chromosome 11, making this the next most common abnormality identified by interphase analysis (2,29,75,76). Early reports identified 11q deletions at 11q13, the location of the BCL-1 (cyclin D1 or CCND1) gene involved in the translocation t(11;14) associated with mantle cell lymphoma (77-80). These reports may have included misclassified mantle cell cases; subsequent studies by the French-American-British system and by immunophenotyping have shown that 11q13 deletions are rare in CLL (81). Regarding affected genes, one small study noted that in 3 of 14 CLL cases examined, there was deletion of MEN1, the tumor suppressor gene associated with multiple endocrine neoplasia syndrome type I, located in the11q13 region (82).

More commonly, 11q deletions involve a 2-3-Mb region at band 11q22.3-q23.1 (83). The 11q14-24 region contains several important genes including ATM (ataxia telangiectasia mutated), RDX (radixin), and FDX1 (ferredoxin 1), with ATM and RDX being potentially important tumor suppressor genes (83). Ataxia telangiectasia is an autosomal recessive disease in which affected individuals have an increased incidence of T-cell lymphoproliferative disorders. Deletions and mutations that lead to disruption of both ATM alleles have been reported in T-cell prolymphocytic leukemia, indicating a tumor suppressor function for the ATM gene product which is lost in this leukemia (84,85).

The ATM gene is located at 11q22-23 (86). There is homology between unmutated ATM protein and proteins controlling cell cycle progression, telomere length, and response to DNA damage (87). The ATM protein normally participates in phosphorylation of p53 protein in response to DNA damage and therefore may play a role in cell cycle regulation and repair of damaged DNA (88).

Decreased ATM protein expression was initially described in association with loss of het-erozygosity at the ATM gene (89). Furthermore, a high proportion (34%) of CLL patients were reported to have decreased levels of ATM protein, even without loss of heterozygosity, and this was associated with shorter survival (89). Analyses demonstrated mutations in the ATM gene, both in patients with 11q deletion and in patients without karyotypic abnormalities (90-92). Furthermore, some of these individuals had germline ATM mutations, suggesting an inherited predisposition to develop CLL (91,92). However, ATM mutations do not seem to account for familial clustering of the disease (93,94).

The leukemia cells of CLL patients with deletions of chromosome 11q may express lower levels of surface adhesion molecules including CD11a/CD18, CD11c/CD18, and CD56 (neural cell adhesion molecule [NCAM]) as well as other function-associated surface proteins, CD31, CD48, and CD58, suggesting that such cells display distinct biological and clinical characteristics (95,96). Deletion of the 11q 23.1 segment is also associated with prolymphocytic morphology (97,98).

Patients with 11q deletions tend to be younger (<55 yr old) and have extensive lymphadenopa-thy, shorter time to treatment, and more aggressive disease than patients without 11q abnormalities (29,75,89,99,100). In patients with 11q deletion, the median survival time is significantly shorter for patients younger than 55 yr. This is in contrast to patients over 55 yr of age, in whom there is no impact of 11q deletion on survival (75). Multivariate survival analysis identified 11q deletion as an independent risk factor for poor prognosis (2). ATM mutation or 11q deletion has been associated with other negative prognostic factors such as CD38 expression and unmutated IgVH genes (32,33,101).

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