We show that the ATM gene is mutated in a fraction of B-CLLs and that mutations can be present in the germ line of patients, suggesting that ATM heterozygotes may be predisposed to B-CLL.
Several candidates, such as mutation of p53 gene and abnormalities of cyclin dependent kinase inhibitor, have been proposed to play an important role in the transformation of a part of B-CLL.
Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL).
The functional evaluation of ataxia telangiectasia mutated (ATM) and p53 was recently developed in B-cell chronic lymphocytic leukaemia (B-CLL), a disease in which the response to DNA damage is frequently altered.
Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed.
In this study, we analyzed 149 bone marrow aspirate or peripheral blood specimens from patients diagnosed with B-CLL, evaluated by four different laboratory studies: morphology examination, three- or four-color flow cytometry analysis, conventional cytogenetics, and fluorescence in situ hybridization (FISH) with a dual-color, break-apart IGH@ probe in addition to a B-CLL FISH probe panel for del(11)(q22) ATM, del(13)(q14.3), del(17)(p13) TP53, and +12.
Deletions in ATM gene region have been found in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) and have been considered as an independent prognosis factor in these pathologies.
To investigate a potential pathogenic role of ATM in B-cell tumorigenesis, we performed mutation analysis of ATM in 29 malignant lymphomas of B-cell origin (B-CLL = 27; mantle cell lymphoma, [MCL] = 2).
In this study, we analyzed 149 bone marrow aspirate or peripheral blood specimens from patients diagnosed with B-CLL, evaluated by four different laboratory studies: morphology examination, three- or four-color flow cytometry analysis, conventional cytogenetics, and fluorescence in situ hybridization (FISH) with a dual-color, break-apart IGH@ probe in addition to a B-CLL FISH probe panel for del(11)(q22) ATM, del(13)(q14.3), del(17)(p13) TP53, and +12.
Relationship between nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) and protein expression of Bcl-2, Bax, Bcl-X and p53.
Sixty-five B-CLL patients were investigated using cytogenetics, interphase fluorescence in situ hybridization (FISH), analysis of IgV(H) and of TP53 mutational status before treatment with 2-chloro-2'-deoxyadenosine (CdA).
Since only in a subset of these cases biallelic inactivation of ATM was observed, we sought to identify other disease-associated genes within 11q22-q23 by analysing NPAT (cell-cycle regulation), CUL5 (ubiquitin-dependent apoptosis regulation) and PPP2R1B (component of the cell-cycle and apoptosis regulating PP2A) for point mutations and their expression in B-CLL by single-strand conformation polymorphism/sequence analysis of the transcripts and real-time polymerase chain reaction.
ATM mutations are also involved in the development of sporadic human cancers such as T-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia.
It is concluded that RS was cytogenetically related with B-CLL in this patient, suggesting the occurrence of a bona fide transformation and that the mutation of p53 exon 7, in association with the development of 17p deletion, possibly played a role in the development of RS.
Noteworthy results were obtained when the group of p53 positive B-CLL patients was analyzed according to the percentage of p53 positive cells (less than 20% and more than 20%, respectively).
Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.