{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:05:32Z","timestamp":1791219932203,"version":"4.1.0"},"reference-count":20,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,9,13]]},"abstract":"<jats:p>\n                    Bruton's tyrosine kinase (BTK) deficiency results in a differentiation block at the pre-B cell stage. Likewise, acute lymphoblastic leukemia cells are typically arrested at early stages of B cell development. We therefore investigated BTK function in B cell precursor leukemia cells carrying a\n                    <jats:italic>BCR-ABL1, E2A-PBX1, MLL-AF4, TEL-AML1<\/jats:italic>\n                    , or\n                    <jats:italic>TEL-PDGFRB<\/jats:italic>\n                    gene rearrangement. Although somatic mutations of the\n                    <jats:italic>BTK<\/jats:italic>\n                    gene are rare in B cell precursor leukemia cells, we identified kinase-deficient splice variants of BTK throughout all leukemia subtypes. Unlike infant leukemia cells carrying an\n                    <jats:italic>MLL-AF4<\/jats:italic>\n                    gene rearrangement, where expression of full-length BTK was detectable in only four of eight primary cases, in leukemia cells harboring other fusion genes full-length BTK was typically coexpressed with kinase-deficient variants. As shown by overexpression experiments, kinase-deficient splice variants can act as a dominant-negative BTK in that they suppress BTK-dependent differentiation and pre-B cell receptor responsiveness of the leukemia cells. On the other hand, induced expression of full-length BTK rendered the leukemia cells particularly sensitive to apoptosis. Comparing BTK expression in surviving or preapoptotic leukemia cells after 10-Gy \u03b3 radiation, we observed selective survival of leukemia cells that exhibit expression of dominant-negative BTK forms. These findings indicate that lack of BTK expression or expression of dominant-negative splice variants in B cell precursor leukemia cells can (\n                    <jats:italic>i<\/jats:italic>\n                    ) inhibit differentiation beyond the pre-B cell stage and (\n                    <jats:italic>ii<\/jats:italic>\n                    ) protect from radiation-induced apoptosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0505196102","type":"journal-article","created":{"date-parts":[[2005,9,2]],"date-time":"2005-09-02T20:34:42Z","timestamp":1125693282000},"page":"13266-13271","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":45,"title":["Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells"],"prefix":"10.1073","volume":"102","author":[{"given":"Niklas","family":"Feldhahn","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"R\u00edo","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonaventure Ndikung Bejeng","family":"Soh","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Liedtke","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke","family":"Sprangers","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Klein","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wernet","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Jumaa","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolf-Karsten","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Hanenberg","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet D.","family":"Rowley","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"M\u00fcschen","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universit\u00e4t, 40225 D\u00fcsseldorf, Germany; Hematopoietic Gene Therapy Program, Centre de Investigaciones Energ\u00e9ticas Medioambientales y Tecnol\u00f3gicas\/Marcelino Botin Foundation, 28040 Madrid, Spain; Max Planck Institute for Immunobiology, 79108 Freiburg, Germany; Department of Hematology and Oncology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2005,9,2]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01608"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031637"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030615"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.101.2.276"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403202"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042101"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.152327399"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020881"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1031503100"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.5.4083-4089.1999"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.4.2613-2621.1999"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.10.3780"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0896-876"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.1997.8.18-2193"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.7.12b.2520"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.1.367"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.11.5988"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1080\/1042819031000067576"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni870"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5278.1096"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0505196102","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T12:39:36Z","timestamp":1649767176000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0505196102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,9,2]]},"references-count":20,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2005,9,13]]}},"alternative-id":["10.1073\/pnas.0505196102"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0505196102","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,9,2]]},"assertion":[{"value":"2005-09-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}