ATM gene and lymphoid malignancies

Abstract

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. Loss of heterozygosity at 11q22-23 (location of the ATM gene) is a frequent event in sporadic lymphoid tumours, and several studies have reported a high prevalence of ATM gene alterations in diverse sporadic lymphoproliferative disorders, adding evidence to the postulated contribution of ATM in the pathogenesis of these tumours. This mini-review will summarize the recently published data concerning the ATM gene in sporadic lymphoid malignancies and will discuss the apparent paradox between the predominance of nonsense mutations observed in patient with ataxia-telangiectasia and the high proportion of missense alterations found in sporadic lymphoid tumours.

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

“…Chromosomal/chromatid breaks and aneuploidy are marks of genetic instability, and we observed an increased frequency of both in B cells from Mdm2 transgenic mice. Humans that lack or have reduced ability to fix DNA breaks or damage and maintain normal chromosomes have high incidences of cancer, particularly lymphoma (Digweed and Sperling, 2004;Gumy-Pause et al, 2004). It is believed that lymphoma frequently develops due to the DNA double-strand breaks and the subsequent errors in ligations that occur during B-and T-cell receptor rearrangements during lymphocyte development (Franco et al, 2006).…”

Serine/threonine phosphatases in the DNA damage response and cancer

“…In some cancers, ATM inhibition benefited the clinical outcome of chemotherapy (Bolderson et al, 2009). In contrast, clinical analyses in many cancer patients show that loss of ATM frequently correlates with resistance to chemotherapy and poor patient survival (Haidar et al, 2000;Gumy-Pause et al, 2004;Austen et al, 2007). Moreover, studies in mouse models suggest that ATM activity can both positively and negatively influence chemotherapy, depending on p53 status (Jiang et al, 2009).…”

Molecular Bases of Ataxia Telangiectasia: One Kinase Multiple Functions

“…The observation that A-T patients display an increased rate of lymphoma and leukaemia onset, has been largely explained by the identification of ATM as a major modulator of the DNA damage response and by the central role that physiological DNA damage plays in the development of the immune system [73][74][75] (see next paragraph "Functional links between ATM kinase and the immune system defects").…”

“…First of all ATM deficiency is clearly associated with an increased onset of tumorigenesis both in human and in mouse models. Indeed, about 20% of A-T patients display a significantly higher incidence in the development of leukaemia and lymphoma, according to the decreased ability of A-T cells to correctly handle the physiological double strand brakes occurring during the maturation of the immune system (reviewed in [73,75]). Consistently, Atm -/-mice develop lymphoma and leukaemia within the first three months of life and die of malignant thymic lymphoma by 4-5 months of age [103][104][105].…”