Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL.
Overall, these data identify a novel molecular mechanism through which ATM kinase may regulate the immune system homeostasis and impair lymphoma development.
We hypothesize that ATM function is slightly attenuated by some variants, which could reduce double-stranded break repair capacity, contributing to the occurrence of translocations and subsequent lymphomas.
The methylation status of the ATM promoter CpG island was determined in 25 samples; ATM protein expression was assessed by Western blot in 9 lymphomas.
Inherited biallelic mutations of the ATM (ataxia-telangiectasia mutated) gene cause ataxia-telangiectasia, a rare autosomal recessive disorder associated with a high incidence of childhood leukaemias and lymphomas, suggesting that ATM gene alterations may be involved in lymphomagenesis.
However, surveys of the ATM mutation status in lymphoma have been limited due to the large size (62 exons) and complex mutational spectrum of this gene.
Germ-line mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with predisposition to lymphoma and acute leukemia.
The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy.
A hemizygous ATM deletion was seen in 44% to 88% of the interphase cells in 15 cases (11.1%); four patients had an indolent lymphoma (follicular center cell lymphoma), and 11 patients had an aggressive lymphoma (five mantle-cell lymphomas [MCLs] and six diffuse large-cell lymphomas).
We have found previously an overrepresentation (3.4%) of ATM mutations in a subset of 88 selected breast cancer patients with a family history of breast cancer, leukemia, and lymphoma.
While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atm-/- p53(-/-) mice develop lymphomas earlier than Atm-/- or p53(-/-) mice, indicating that mutations in these two genes lead to synergy in tumorigenesis.
The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-cell prolymphocytic leukemia (T-PLL), which is often associated with cytogenetic aberrations of chromosome 14.
Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking PRF1 missense mutations to lymphoma susceptibility and highlighting clinical variability within families.
Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome.
Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apc tumor suppressor.
Patients with abdominal nodal disease had inferior lymphoma specific survival (p=0.04) and presented with higher age adjusted IPI (p<0.001), lactate dehydrogenase (p<0.001) and more often advanced stage (p<0.001), bulky disease (p<0.001), B-symptoms (p<0.001), and double expression of MYC and BCL2 (p=0.02) compared to patients without nodal abdominal involvement, but less often extranodal involvement (p<0.02).