Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement

Abstract

The possible involvement of germline mutation of the ataxia telangiectasia mutated (ATM) gene in childhood acute leukemia with mixed lineage leukemia (MLL) gene rearrangement (MLL ؉ ) was investigated. Of the 7 patients studied, 1 showed a germline missense ATM mutation (8921C>T; Pro2974Leu), located in the phosphatidylinositol-3 (PI-3) kinase domain. In reconstitution assays, the ATM mutant 8921T could only partially rescue the radiosensitive phenotype of AT fibroblasts, and in an in vitro kinase assay, it showed a defective phosphorylation of p53-Ser15. Furthermore, the introduction of 8921T in IntroductionAtaxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. The responsible gene, ATM (ataxia telangiectasia mutated), is located on chromosome 11q22-23 and encodes a 350-kDa nuclear protein with a carboxy-terminal domain similar to the catalytic subunit of the phosphatidylinositol-3 kinases (PI-3 kinases). 1-3 PI-3 kinase-related proteins are known to function in the maintenance of genomic stability, cell cycle control, and cellular responses to DNA damage. 4,5 AT cells exhibit hypersensitivity to ionizing radiation and are defective at multiple cell cycle checkpoints. [4][5][6][7] It is well established that patients with AT are at increased risk of cancer, 8 in particular, neoplasms of lymphoid origin. 9,10 Somatic mutations in the ATM gene have been identified in patients with T-cell prolymphocytic leukemia (T-PLL) 11 and B-cell chronic lymphocytic leukemia (B-CLL) with no family history of AT. [12][13][14] Mutations observed in these reports are missense mutations and most occur in the PI-3 kinase domain. Heterozygous germline missense mutations were also found among B-CLL patients, indicating that such genetic alterations might act as predisposing factors for the development of lymphoid tumors. 12,13 The germline missense ATM mutations have been reported in patients with breast carcinoma with early onset disease and positive family history. 15 The chromosomal translocation of the mixed lineage leukemia (MLL) gene at 11q23 is involved in a subset of childhood leukemia, most frequently in infantile leukemia. [16][17][18] The MLL gene rearrangement is also involved in treatment-related leukemias secondary to chemotherapy using topoisomerase II (topo II) inhibitors. This has led to the hypothesis that in utero exposure to chemicals, such as certain antibiotics, laxatives, podophyllin resins, flavonoids, herbal medicines, and benzene metabolites may cause infantile leukemia via an effect on topo II. 19,20 Recent epidemiologic data indicate that maternal alcohol exposure and exposure to recreational drugs, pesticides, and anti-inflammatory drugs increase the risk of infantile leukemia. [21][22][23] Thus, environmental factors appear to play an important role in the development of this disease.Previous studies have shown that AT cells are hypersensitive to topo II inhibitors. [24][25][26][27][28] It is plausible that m...

Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-κB survival pathway signaling

“…To date, reports on the frequency of ATM mutation in pediatric ALL are not consistent; they vary from complete absence to an incidence of 20%. [10][11][12][13][14] Although our findings suggest that defects in the p53 response, through defective activation or mutation, are relatively rare in pediatric ALL, they cause a severe clinical phenotype.…”

“…Interestingly, in pediatric ALL, the incidence of TP53 mutation is notably low, with less than 5% of tumors at diagnosis harboring detectable mutations. 7,8 Although the rate of mutation at relapse is slightly higher, 9 indicating a role for p53 inactivation in drug resistance, genes other than p53 that impinge on its function, such as ATM, [10][11][12][13][14] MDM2, p21, BCL2, and BAX, [15][16][17][18][19][20][21][22] might be involved in tumor progression. Furthermore, given that the balance between proapoptotic and prosurvival signals is critical in determining cell fate after DNA damage, 5 distinct pathways activated in response to DNA damage may alternatively be deregulated.…”

ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells

“…6 More interestingly, ATM expression is aberrantly low in several B-and T-cell lymphomas irrespective of A-T genotype. [7][8][9][10] Fas (CD95/APO-1) is a transmembrane protein belonging to the tumor necrosis factor superfamily. Upon binding of Fas ligand or agonistic antibodies, the Fas receptor recruits several cytosolic proteins to form the death-inducing signaling complex (DISC).…”

Molecular variants of the ATM gene in Hodgkin's disease in children

“…This could suggest a dominant-negative mechanism, as was demonstrated by Scott et al (2002); some missense mutations that reside outside the PI3-K region have an effect on ATM downstream targets by a dominant-negative mechanism. In a more recent study by Oguchi et al (2003), the dominant-negative effect of a missense mutation located in the PI3-K domain was demonstrated in a childhood acute leukaemia patient with MLL rearrangement.…”