{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:49:56Z","timestamp":1791355796108,"version":"4.3.1"},"reference-count":40,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1,1]]},"abstract":"<jats:p>B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease involving more than one molecular mechanism that leads to the transformation of CD5+ B cells at either the pregerminal or postgerminal center stage of differentiation. It was previously demonstrated that ataxia telangiectasia mutated (ATM) gene mutations can occur in B-CLL and cause a defect in the p53 pathway. Here the role of ATM mutations in the pathogenesis of B-CLL is addressed. Of 50 B-CLL tumors with fully analyzedATM and TP53, 16 had ATM mutations. Six of 50 B-CLLs showed mutations in TP53 and the remaining 28 tumors had wild-type ATM or TP53. No tumor had both ATM and TP53 mutations. Remarkably, all 16 ATM mutant B-CLLs showed the absence of somatic variable region heavy chain hypermutation indicating a pregerminal center cell origin and a common pathogenesis for these tumors. Furthermore, in 5 of the 16 B-CLLs, ATMmutation preceded the transformation stage of differentiation. At the cellular level, ATM mutant tumors exhibited a deficient ATM-dependent p53 response to gamma irradiation, failure to up-regulate TRAIL-R2, a downstream target that links irradiation-induced p53 response with apoptosis, and an inability to repair induced chromosome breaks. Mantle cell lymphoma (MCL) is also of pregerminal center origin and ATMmutations are frequent in this malignancy. It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.<\/jats:p>","DOI":"10.1182\/blood.v99.1.300","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T08:46:40Z","timestamp":1027759600000},"page":"300-309","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":106,"title":["Ataxia telangiectasia mutated\u2013deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage"],"prefix":"10.1182","volume":"99","author":[{"given":"Tatjana","family":"Stankovic","sequence":"first","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant S.","family":"Stewart","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Fegan","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Biggs","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Last","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Byrd","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell D.","family":"Keenan","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A. H.","family":"Moss","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M. R.","family":"Taylor","sequence":"additional","affiliation":[{"name":"From the University of Birmingham, CRC Institute for Cancer Studies, The Medical School, Edgbaston; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021217344231300_B1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/00001622-200001000-00004","article-title":"Update on the biology of chronic lymphocytic leukaemia.","volume":"12","author":"Bannerji","year":"2000","journal-title":"Curr Opin Oncol."},{"key":"2020021217344231300_B2","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1182\/blood.V94.6.1848","article-title":"Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukaemia.","volume":"94","author":"Hamblin","year":"1999","journal-title":"Blood."},{"key":"2020021217344231300_B3","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1182\/blood.V94.6.1840","article-title":"Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukaemia.","volume":"94","author":"Damle","year":"1999","journal-title":"Blood."},{"key":"2020021217344231300_B4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1600-065X.1987.tb00507.x","article-title":"Mutation drift and repertoire shift in the maturation of the immune response.","volume":"96","author":"Berek","year":"1987","journal-title":"Immunol Rev."},{"key":"2020021217344231300_B5","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1182\/blood.V87.2.423.bloodjournal872423","article-title":"Leukaemia and lymphoma in ataxia telangiectasia.","volume":"87","author":"Taylor","year":"1996","journal-title":"Blood."},{"key":"2020021217344231300_B6","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1146\/annurev.genet.31.1.635","article-title":"Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart.","volume":"31","author":"Shiloh","year":"1997","journal-title":"Ann Rev Genet."},{"key":"2020021217344231300_B7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/ng0997-96","article-title":"Clustering of missense mutations in the ataxia telangiectasia gene in a sporadic T cell leukaemia.","volume":"17","author":"Vorechovsky","year":"1997","journal-title":"Nature Genet."},{"key":"2020021217344231300_B8","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/nm1097-1155","article-title":"Biallelic mutations in the ATM gene in T-prolymphocytic leukaemia.","volume":"3","author":"Stilgenbauer","year":"1997","journal-title":"Nature Med."},{"key":"2020021217344231300_B9","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.1182\/blood.V91.10.3920.3920_3920_3926","article-title":"Inactivation of the ATM gene in T-cell prolymphocytic leukaemia.","volume":"91","author":"Stoppa-Lyonnet","year":"1998","journal-title":"Blood."},{"key":"2020021217344231300_B10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S0140-6736(98)10117-4","article-title":"Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia.","volume":"353","author":"Stankovic","year":"1999","journal-title":"Lancet."},{"key":"2020021217344231300_B11","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1182\/blood.V98.3.814","article-title":"p53 dysfunction in B-cell chronic lymphocytic leukaemia: inactivation of ATM as an alternative to TP53 mutation.","volume":"98","author":"Pettitt","year":"2001","journal-title":"Blood."},{"key":"2020021217344231300_B12","first-page":"24","article-title":"ATM mutations in B-cell chronic lymphocytic leukemia.","volume":"59","author":"Bullrich","year":"1999","journal-title":"Cancer Res."},{"key":"2020021217344231300_B13","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1182\/blood.V94.2.748","article-title":"Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia.","volume":"94","author":"Schaffner","year":"1999","journal-title":"Blood."},{"key":"2020021217344231300_B14","doi-asserted-by":"crossref","first-page":"4990","DOI":"10.1182\/blood.V87.12.4990.bloodjournal87124990","article-title":"National Cancer Institute-sponsored working group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.","volume":"87","author":"Cheson","year":"1996","journal-title":"Blood."},{"key":"2020021217344231300_B15","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1086\/301706","article-title":"ATM mutations and phenotypes in A-T families in the British Isles: expression of mutant ATM and the risk of leukaemia, lymphoma and breast cancer.","volume":"62","author":"Stankovic","year":"1998","journal-title":"Am J Hum Genet."},{"key":"2020021217344231300_B16","first-page":"470","article-title":"Restriction endonuclease fingerprinting (REF): a sensitive method for screening mutations in long, contiguous segments of DNA.","volume":"18","author":"Liu","year":"1995","journal-title":"BioTechniques."},{"key":"2020021217344231300_B17","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0167-5699(95)80166-9","article-title":"The human immunoglobulin VH repertoire.","volume":"16","author":"Cook","year":"1995","journal-title":"Immunol Today."},{"key":"2020021217344231300_B18","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ng0193-88","article-title":"Structure and physical map of 64 variable segments in the 3\u20320.8-megabase region of the human immunoglobulin heavy-chain locus.","volume":"3","author":"Matsuda","year":"1993","journal-title":"Nature Genet."},{"key":"2020021217344231300_B19","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1038\/sj.onc.1202656","article-title":"Mutations in serines 15 and 20 of human p53 impair its apoptotic activity.","volume":"18","author":"Unger","year":"1999","journal-title":"Oncogene."},{"key":"2020021217344231300_B20","doi-asserted-by":"crossref","first-page":"6411","DOI":"10.1038\/sj.onc.1203025","article-title":"Induction of the TRAIL receptor KILLER\/DR5 in p53-dependent apoptosis but not growth arrest.","volume":"18","author":"Wu","year":"1999","journal-title":"Oncogene."},{"key":"2020021217344231300_B21","first-page":"4552","article-title":"Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia.","volume":"58","author":"Starostik","year":"1998","journal-title":"Cancer Res."},{"key":"2020021217344231300_B22","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1093\/hmg\/8.1.69","article-title":"Characterization of ATM gene mutations in 66 ataxia telangiectasia families.","volume":"1","author":"Sandoval","year":"1999","journal-title":"Hum Mol Genet."},{"key":"2020021217344231300_B23","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1093\/hmg\/10.11.1155","article-title":"hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay.","volume":"10","author":"Pitts","year":"2001","journal-title":"Hum Mol Genet."},{"key":"2020021217344231300_B24","doi-asserted-by":"crossref","first-page":"30133","DOI":"10.1074\/jbc.M103160200","article-title":"Residual ATM protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-&gt;G mutations, showing a less severe phenotype.","volume":"276","author":"Stewart","year":"2001","journal-title":"J Biol Chem."},{"key":"2020021217344231300_B25","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/sj.bjc.6690209","article-title":"Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia.","volume":"79","author":"Inskip","year":"1999","journal-title":"Br J Cancer."},{"key":"2020021217344231300_B26","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/35077207","article-title":"Cancer genetics.","volume":"411","author":"Ponder","year":"2001","journal-title":"Nature."},{"key":"2020021217344231300_B27","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/sj.leu.2401531","article-title":"Linkage analysis for ATM in familial B cell chronic lymphocytic leukaemia.","volume":"10","author":"Bevan","year":"1999","journal-title":"Leukemia."},{"key":"2020021217344231300_B28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/0165-4608(90)90245-6","article-title":"Cancers in 44 families with ataxia telangiectasia.","volume":"50","author":"Morrell","year":"1990","journal-title":"Cancer Genet Cytogenet."},{"key":"2020021217344231300_B29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/jnci\/93.2.121","article-title":"Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries.","volume":"93","author":"Olsen","year":"2001","journal-title":"J Natl Cancer Inst."},{"key":"2020021217344231300_B30","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/ijc.1329","article-title":"Cancer risk in heterozygotes for ataxia-telangiectasia.","volume":"93","author":"Geoffroy-Perez","year":"2001","journal-title":"Int J Cancer."},{"key":"2020021217344231300_B31","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1182\/blood.V96.1.374a","article-title":"No germline ATM mutation in a series of 16 T-cell prolymphocytic leukemias.","volume":"96","author":"Stoppa-Lyonnet","year":"2000","journal-title":"Blood."},{"key":"2020021217344231300_B32","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1056\/NEJM199708213370804","article-title":"Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.","volume":"337","author":"Ichikawa","year":"1997","journal-title":"N Engl J Med."},{"key":"2020021217344231300_B33","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1023\/A:1008265304712","article-title":"Intraclonal molecular heterogeneity suggests a hierarchy of pathogenic events in Burkitt's lymphoma.","volume":"8","author":"Gutierrez","year":"1997","journal-title":"Ann Oncol."},{"key":"2020021217344231300_B34","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1182\/blood.V91.11.4342","article-title":"p53 expression in B cell chronic lymphocytic leukaemia: a marker of disease progression and poor prognosis.","volume":"91","author":"Cordone","year":"1998","journal-title":"Blood."},{"key":"2020021217344231300_B35","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1046\/j.1365-2141.1997.4723278.x","article-title":"p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis.","volume":"99","author":"Lens","year":"1997","journal-title":"Br J Haematol."},{"key":"2020021217344231300_B36","first-page":"1","article-title":"Tumors associated with p53 germline mutations: a synopsis of 91 families.","volume":"150","author":"Kleihues","year":"1997","journal-title":"Am J Pathol."},{"key":"2020021217344231300_B37","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1073\/pnas.050400997","article-title":"Mantle cell lymphoma is characterised by inactivation of the ATM gene.","volume":"97","author":"Schaffner","year":"2000","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021217344231300_B38","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/j.1365-2141.1995.tb05167.x","article-title":"Atypical chronic lymphocytic leukaemia with t(11;14)(q13;q32): karyotype evolution and prolymphocytic transformation.","volume":"90","author":"Cuneo","year":"1995","journal-title":"Br J Haematol."},{"key":"2020021217344231300_B39","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/(SICI)1098-2264(200003)27:3<285::AID-GCC9>3.0.CO;2-M","article-title":"t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B cell chronic lymphocytic leukaemia.","volume":"27","author":"Bentz","year":"2000","journal-title":"Genes Chromosomes Cancer."},{"key":"2020021217344231300_B40","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1182\/blood.V96.5.1940","article-title":"Abnormal rearrangement within the \u03b1\/\u03b4 T-cell receptor locus in lymphomas from ATM-deficient mice.","volume":"96","author":"Liyanage","year":"2000","journal-title":"Blood."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/99\/1\/300\/1679471\/h80102000300.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/99\/1\/300\/1679471\/h80102000300.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T18:30:03Z","timestamp":1581532203000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/99\/1\/300\/107261\/Ataxia-telangiectasia-mutateddeficient-Bcell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,1,1]]},"references-count":40,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2002,1,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.v99.1.300","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2002,1,1]]}}}