Deletions of Bands 11q22q23 With ATM As the Candidate Gene

In a study using FISH, a critical region was identified around the neural cell adhesion molecule (NCAM) gene in band 11q23.1 in 15 hematological tumors (51). In another study, the extent of 11q deletions among 40 B-CLL cases was determined using a FISH probe set of overlapping yeast artificial chromosome (YAC) clones spanning bands 11q14-q24 (52,53). All aberrations affected a minimal consensus region of 2-3 Mb in size in bands 11q22.3-q23.1. In the minimal deleted region, the ataxia telangiectasia mutated (ATM) gene was localized, which, owing to its role in DNA repair and the frequent observation of lymphomas in ATM knockout mice, appeared to be a candidate tumor suppressor gene (54,55). In fact, the changes in both ATM alleles by deletion and/or mutation in the sense of the two-hit hypothesis of tumor suppressor gene inactivation could be demonstrated for the first time in human tumors in T-prolymphocytic leukemia (T-PLL) (56,57). Because of a lack of ATM protein expression, the involvement of ATM in B-CLL was also postulated, and inactivation of ATM by deletion and/or mutation could actually be demonstrated (58-61). It was shown that ATM mutant B-CLL cases exhibited a deficient ATM-dependent response of p21 to y-irradiation, failure to upregulate tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), and inability to repair induced chromosomal breaks (62). An association of deletion 11q with a more aggressive clinical course of B-CLL was suggested in a chromosome banding study (63). Interestingly, all ATM mutant cases showed absence of somatic VH hypermutation (see also Subheading 2.8. below), indicating that ATM may play a role at the pregerminal center stage of B-cell maturation and may lead to the development of B-CLL derived from pregerminal center cells (10,64). However, mutation of the remaining ATM allele was found only in 5 of 22 B-CLL cases with 11q22-q23 deletion of our series, which indicates a possible involvement of additional genes in this region in B-CLL (59). By contrast, in mantle cell lymphoma, in which the 11q22-q23 deletion occurs in nearly half the cases (65,66), mutation of the remaining allele could be demonstrated in all cases with deletion of an ATM allele (67). Thus, ATM appears to be the tumor suppressor gene inactivated in connection with 11q22-q23 deletions in T-PLL, mantle cell lymphoma, and some cases of B-CLL. Elucidation of the situation in B-CLL cases with 11q deletion without mutation in the remaining ATM allele is currently in progress.

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