Mantle cell lymphoma is characterized by inactivation of the ATM gene

Abstract

In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the chromosomal region 11q22-q23 has been identified as a frequent event in this type of cancer, indicating the existence of a pathogenically relevant tumor suppressor gene in this region. The deleted segment contains the ATM (ataxia telangiectasia mutated) gene. ATM is an interesting candidate as a tumor suppressor gene because constitutive inactivation of the gene predisposes ataxia telangiectasia patients to lymphoid malignancies. To assess the potential involvement of the gene in MCL lymphomagenesis, we performed mutation analysis of ATM in 12 sporadic cases of MCL, 7 of them with a deletion of one ATM gene copy, by using single-strand conformation polymorphism analysis of reverse transcription-PCR-amplified mRNA and subsequent DNA sequencing. In all seven cases containing a deletion of one ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, truncation, or alteration of the protein. In addition, biallelic ATM mutations were identified in two MCLs that did not contain 11q deletions. Interestingly, in three cases analyzed, the ATM mutations detected in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germ-line origin. The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicates that ATM plays a role in the initiation and͞or progression of MCL.

Loss of chromosome 11q21–23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell non-Hodgkin’s lymphoma

“…Suggested candidates for tumour suppressor genes and protooncogenes at the chromosomal regions which are frequently lost and gained, respectively, include the ATM gene at 11q23.1 (Bullrich et al, 1999;Schaffner et al, 2000), the TP53 gene at 17p13.1 (Stokke et al, 2000), and the BCL-2 gene at 18q21 (Monni et al, 1997). Other tumour suppressor genes and protooncogenes, which are located within the frequently altered regions, include p16INK4a (9p21), RB-1 (13q14), BCL6 (3q27), CCND3 (6p), and c-MYC (8q24).…”

Immunoglobulin V somatic hypermutation in mantle cell lymphoma: mutated genotype correlates with better clinical outcome

“…3,4 Recent studies, including a number of oligonucleotide array studies, revealed additional biochemical abnormalities in mantle cell lymphoma, such as defects in the apoptotic pathway, cell cycle progression and DNA repair. [5][6][7][8][9][10] To further understand the biology of this type of B-cell neoplasm, one approach is to examine the somatic hypermutation of the variable region of the immunoglobulin heavy chain (V H ) gene. In chronic lymphocytic leukemia, it has been shown that a subset of cases has relatively high levels of V H somatic mutation, and mutated cases were associated with better clinical outcome when using o98% homology as the cutoff.…”

Mantle cell lymphomas with clonal immunoglobulin V3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin V genes

“…This region harbors the DNA damagesensing ATM (ataxia telangiectasia mutated) gene and it has previously been shown that loss of one allele and mutation of the remaining allele is associated with progressive disease. 21 Located in the adjacent chromosomal region, 11 Mb telomeric to ATM, is the gene encoding histone H2AX. This protein is suggested to be a genomic caretaker requiring both alleles for full tumor-protective function.…”