Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

• MeSH
• ATM protein * genetika   MeSH
• dítě MeSH
• dospělí MeSH
• hematologické nádory * genetika   mortalita   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• teleangiektatická ataxie * genetika   komplikace   mortalita   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein * MeSH

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

• Klíčová slova
• Eye movement recordings, Hereditary ataxia, Oculomotor, Recommendations, Systematic review, Vestibular,
• MeSH
• ataxie MeSH
• Friedreichova ataxie * MeSH
• genotyp MeSH
• lidé MeSH
• pohyby očí MeSH
• progrese nemoci MeSH
• spinocerebelární degenerace * MeSH
• teleangiektatická ataxie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL. METHODS: We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion. RESULTS: Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays. CONCLUSION: Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.

• MeSH
• ATM protein * genetika   MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• lidé MeSH
• mutace MeSH
• nádorové supresorové proteiny genetika   MeSH
• protein-serin-threoninkinasy genetika   terapeutické užití   MeSH
• proteiny buněčného cyklu genetika   MeSH
• teleangiektatická ataxie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein * MeSH
• nádorové supresorové proteiny MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH

The MRN (MRE11-RAD50-NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations of the MRN complex subunit MRE11 cause the hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. Conversely, the PIH1D1 phospho-binding domain PIH-N is required for association with MRE11 phosphorylated by CK2. Consistent with these findings, depletion of PIH1D1 resulted in MRE11 destabilization and affected DNA-damage repair processes dependent on MRE11. Additionally, mutations of serines 688/689, which abolish PIH1D1 binding, also resulted in decreased MRE11 stability. As depletion of R2TP frequently leads to instability of its substrates and as truncation mutation of MRE11 lacking serines 688/689 leads to decreased levels of the MRN complex both in ATLD patients and an ATLD mouse model, our results suggest that the MRN complex is a novel R2TP complex substrate and that their interaction is regulated by CK2 phosphorylation.

• MeSH
• ATM protein metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• enzymy opravy DNA metabolismus   MeSH
• fosforylace fyziologie   MeSH
• jaderné proteiny metabolismus   MeSH
• kaseinkinasa II metabolismus   MeSH
• lidé MeSH
• mutace fyziologie   MeSH
• myši MeSH
• oprava DNA fyziologie   MeSH
• poškození DNA fyziologie   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• proteiny tepelného šoku metabolismus   MeSH
• ribonukleoproteiny malé jadérkové metabolismus   MeSH
• RNA-polymerasa II metabolismus   MeSH
• serin metabolismus   MeSH
• teleangiektatická ataxie metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• vazba proteinů fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• enzymy opravy DNA MeSH
• jaderné proteiny MeSH
• kaseinkinasa II MeSH
• proteiny regulující apoptózu MeSH
• proteiny tepelného šoku MeSH
• ribonukleoproteiny malé jadérkové MeSH
• RNA-polymerasa II MeSH
• serin MeSH
• TOR serin-threoninkinasy MeSH

The main aim of current cancer research is to find a way to selectively affect the tumor cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy, ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also resistance of tumor cells to DNA damaging agents, through stress support under replication stress. Thus, the inhibition of ATR leads to increased effectiveness of cancer therapy and in addition enables highly selective targeting of cancer cells through synthetic lethal interactions. Despite this great potential, only a few potent and selective inhibitors of ATR kinase have been developed to date. However, those which have been developed provide great promise, and are under evaluation in many current preclinical and clinical trials. The purpose of this review is to summarize the potential of ATR inhibitors and the medicinal chemistry efforts which resulted in their identification.

• MeSH
• ATM protein metabolismus   MeSH
• knihovny malých molekul metabolismus   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• signální transdukce účinky léků   MeSH
• teleangiektatická ataxie prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• knihovny malých molekul MeSH

Ataxia telangiectasia (AT) is a genomic instability syndrome characterised, among others, by progressive cerebellar degeneration, oculocutaneous telangiectases, immunodeficiency, elevated serum alpha-phetoprotein level, chromosomal breakage, hypersensitivity to ionising radiation and increased cancer risk. This autosomal recessive disorder is caused by mutations in the ataxia telangiectasia mutated (ATM) gene coding for serine/threonine protein kinase with a crucial role in response to DNA double-strand breaks. We characterised genotype and phenotype of 12 Slavic AT patients from 11 families. Mutation analysis included sequencing of the entire coding sequence, adjacent intron regions, 3'UTR and 5'UTR of the ATM gene and multiplex ligation-dependent probe amplification (MLPA) for the detection of large deletions/duplications at the ATM locus. The high incidence of new and individual mutations demonstrates a marked mutational heterogeneity of AT in the Czech Republic. Our data indicate that sequence analysis of the entire coding region of ATM is sufficient for a high detection rate of mutations in ATM and that MLPA analysis for the detection of deletions/duplications seems to be redundant in the Slavic population.

• MeSH
• ATM protein MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   MeSH
• lidé MeSH
• mladiství MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• nádorové supresorové proteiny genetika   MeSH
• předškolní dítě MeSH
• protein-serin-threoninkinasy genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• teleangiektatická ataxie genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• nádorové supresorové proteiny MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH

Cellular senescence is a condition of longlasting proliferation arrest, induced in cells in response to various stressors. These stressors include telomere shortening and/or dysfunction, DNA damage, and oncogene signalling. Epithelial and mesenchymal cells and also tumour cells derived from these tissues are more resistant to radiation-induced apoptosis and respond to irradiation mainly by senescence. Senescence-associated molecular mechanisms related to the activation of canonical DNA damage pathway ATM-p53 as well as mechanisms related to the extracellular signals, cytokine increase and upregulation of their receptors are discussed in this review.

• MeSH
• biologické modely MeSH
• ionizující záření * MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory vyvolané zářením genetika   MeSH
• poškození DNA MeSH
• signální transdukce MeSH
• stárnutí buněk genetika   MeSH
• teleangiektatická ataxie genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH

Ataxia-telangiectasia mutated kinase (ATM) is a DNA damage-inducible protein kinase, which phosphorylates plethora of substrates participating in DNA damage response. ATM significance for the cell faith is undeniable, since it regulates DNA repair, cell-cycle progress, and apoptosis. Here we describe its main signalling targets and discuss its importance in DNA repair as well as novel findings linked to this key regulatory enzyme in the terms of ionizing radiation-induced DNA damage.

• MeSH
• ATM protein MeSH
• buněčný cyklus fyziologie   MeSH
• DNA vazebné proteiny genetika   fyziologie   MeSH
• lidé MeSH
• mutace * MeSH
• nádorové supresorové proteiny genetika   fyziologie   MeSH
• oprava DNA fyziologie   MeSH
• poškození DNA účinky záření   MeSH
• protein-serin-threoninkinasy genetika   fyziologie   MeSH
• proteiny buněčného cyklu genetika   fyziologie   MeSH
• teleangiektatická ataxie genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• nádorové supresorové proteiny MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH

Complete or partial inability to sense and repair DNA damage increases the risk of developing cancer. The ataxia telangiectasia mutated (ATM) protein kinase has a crucial role in response to DNA double-strand breaks. Hereditary mutations in the ATM gene are the cause of a rare genomic instability syndrome ataxia telangiectasia (AT) characterized, among others, by elevated cancer risk. Although clear in homozygotes, numerous studies have failed to find a link between heterozygotes and cancer. However, there is increasing evidence that ATM heterozygotes have an increased risk of developing breast cancer. First, epidemiological studies conferred an increased risk of breast cancer among AT relatives. Second, in vitro studies of heterozygous cells provide strong evidence of hyperradiosensitivity. Third, some clinical studies found an increased frequency of ATM mutations among high-risk breast cancer families.

• MeSH
• ATM protein MeSH
• DNA vazebné proteiny fyziologie   MeSH
• lidé MeSH
• mutace MeSH
• nádorové supresorové proteiny fyziologie   MeSH
• nádory prsu etiologie   MeSH
• protein-serin-threoninkinasy fyziologie   MeSH
• proteiny buněčného cyklu fyziologie   MeSH
• teleangiektatická ataxie genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• nádorové supresorové proteiny MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH

We refer 55 cases of the chromosomal instability syndromes (SCI), diagnosed in patients of our genetical clinics. Problems of early diagnosis can be documented by a discrepancy between the expected number of patients and their relative advanced age at the time when SCI was ascertained. We have also shown that NBS patients can be diagnosed earlier and the disease sufficiently confirmed on the basis of congenital microcephaly and on the direct detection of 657de15 mutation in NBS1 gene. Genealogical analysis of families with SCI revealed a low risk of prenatal selection of affected homozygotes and high cancer prevalence in relative (in NBS families recognized heterozygotes) at young adult age. Due to severe DNA repair disorder and hyperradiosensitivity of affected homozygotes as well as unaffected heterozygotes, conventional diagnostics and treatment protocols of lymphoreticular malignancies in affected homozygotes are prohibited. The use of Nijmegen treatment protocol improved in our patients dramatically their clinical prognosis, which is documented by 6 NBS patients surviving one or two malignancies. Early diagnose of SCI and information for families and their doctors about consequences of DNA repair disorder and about their hyperradiosensitivity is essential for improving the clinical prognosis of SCI patients.

• MeSH
• Bloomův syndrom genetika   MeSH
• chromozomální poruchy diagnóza   genetika   MeSH
• dospělí MeSH
• Fanconiho anemie genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetné abnormality genetika   MeSH
• nádory komplikace   genetika   MeSH
• oprava DNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• syndrom MeSH
• teleangiektatická ataxie genetika   MeSH
• zlomy chromozomů * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH